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Prevalence of gout with comorbidity aggregations in southern Taiwan
Joint Bone Spine 82 (2015) 45–51
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Original article
Prevalence of gout with comorbidity aggregations in southern Taiwan Fang-Yi Tu a,1 , Gau-Tyan Lin b,c,d,1 , Su-Shin Lee e,f , Yi-Ching Tung g , Hung-Ping Tu g,∗,2 , Hung-Che Chiang h,i,2 a
Public Health Bureau, Pingtung County Government, Pingtung, Taiwan Department of Orthopedic Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan Kaohsiung Municipal United Hospital, Kaohsiung, Taiwan d Graduate Institute of Medicine, College of Medicine, Kaohsiung, Taiwan e Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan f Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan g Department of Public Health and Environmental Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung, Taiwan h Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Miaoli, Taiwan i Department of Occupational Medicine, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan b c
a r t i c l e
i n f o
Article history: Accepted 1st July 2014 Available online 17 September 2014 Keywords: Gout Comorbidity Prevalence Comorbidity aggregations
a b s t r a c t Objective: Comorbidity is an important concern for chronic gout patients. We evaluated the relationship between comorbidity profiles and gout in Taiwan aborigines and Taiwanese Han. Methods: We used the claims data from the Taiwan national health insurance database for 2004 to 2006. Physician-diagnosed gout and comorbidities were coded using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Total sampling from Pingtung County of southern Taiwan included 37,482 aborigines (gout cases, n = 3906 and controls, n = 33,576) and 37,451 Han (gout cases, n = 1115 and controls, n = 36,336). Results: In 2006, the gout prevalences were 10.42% and 2.98% (prevalence ratio [PR] = 3.50) in the aborigines and Han general populations, respectively. The prevalences of uric acid nephrolithiasis and tophi were higher in aborigines (0.42% and 0.30%, respectively) than in Han (0.09% and 0.04%, respectively). When stratified by comorbidity status, the prevalences of gout were 4.49% and 27.34% in aborigines and 1.52% and 9.44% in Han (approximate PR = 3.00). Similarly, the prevalence ratios of gout in the comorbidity group, compared with the non-comorbidity group, were 6.09 in aborigines and 6.23 in Han. Multivariate odds ratios [ORs] showed that hypercholesterolemia, hyperglyceridemia, essential hypertension and renal insufficiency were the common comorbidities of gout (OR ≥ 1.63); heart failure exerted a significant effect only in aborigines (OR = 1.55). For five comorbidity factors, patients with multiple comorbidities had higher gout prevalence (maximum OR = 12.90). Conclusion: Gout prevalence was higher in aborigines, both with and without comorbidities, than in Han. The comorbid diseases and comorbidity aggregations showed a substantial association with gout occurrence in both ethnicities. © 2014 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction Gout is characterized by monosodium urate deposits in the soft tissues of hyperuricemic patients [1]. Clinical symptoms involve recurrent flares of acute arthritis, chronic arthropathy, tophi, uric acid urolithiasis, and renal impairment [1,2]. The affected joints
∗ Corresponding author. Tel.: +886 7 31 21 101; fax: +886 7 322 75 08. E-mail address: [email protected] (H.-P. Tu). 1 These 2 authors contributed equally to this work. 2 These 2 authors contributed equally to this work.
often undergo cartilage degeneration, marginal bone erosion, and synovial proliferation [1–3]. Acute flares of gouty arthritis are disabling, excruciating, and sudden. These flares produce burning pain, swelling, redness, warmth, and stiffness in the affected joint and require rapid, effective, and safe treatments [2,3]. Gout is the most prevalent inflammatory arthritis in developed countries [4]. Gout also occurs in rapidly westernized populations, in particular, among indigenous groups or migrants from rural to urban communities [5]. Epidemiologic data indicate that the prevalence of gout is rising and is greater than that of rheumatoid disease in men over 40 years of age in the US [6]. In addition to a higher incidence of gout, patient care has evolved over the past 20 years [7]. In
http://dx.doi.org/10.1016/j.jbspin.2014.07.002 1297-319X/© 2014 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
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F.-Y. Tu et al. / Joint Bone Spine 82 (2015) 45–51
the Taiwan general population from 2000 to 2008, the prevalence of rheumatoid arthritis was 52.4 per 100,000 persons, and the incidence was 17.3 per 100,000 person-years [8]. A multicenter study of UK general practices showed a 3-fold rise in gout occurrence between the 1970s and the 1990s (from 0.03 to 0.095%) [9] and a 1.4% rise from 2000 to 2005 compared to IMS databases from Germany and UK [10]. A US National Health and Nutrition Examination Survey [NHANES] showed that the prevalence of gout among adults was 3.9% in 2007–2008 [4]. In the UK general population from 1997 to 2012, the prevalence of gout was 2.49% and the incidence of gout was 1.77 per 1000 person-years, with a 63.9% increase in prevalence and a 29.6% increase in incidence [11]. In Taiwan, the gout prevalence was 4.62% in 2004 from the National Health Insurance (NHI) database [12]. In Mainland China, the gout prevalence had risen to 1.14% in 2004 from 0.36% in 2002 [13,14]. Among Polynesian peoples, such as the New Zealand Maoris, the prevalences of hyperuricemia and gout are 27.1% and 13.9%, respectively, in men and 26.6% and 2%, respectively, in women [15]. In highland Taiwan aborigines, the presence of hyperuricemia can be as high as 41–82% and the prevalence of gout as high as 2–20% [16,17]. Associations between gout and hypertension, diabetes, kidney disease, and cardiovascular disease have been observed since the late 19th century [18]. Gout is frequently associated with older age [19]. In aging populations, patients tend to be sicker and to have more comorbid illness, including diabetes mellitus, heart failure, hypertension, hypercholesterolemia, hyperglyceridemia, obesity and chronic kidney disease [1,20–24]. Clinical strategies for the management of gout must include consideration of these and other common cardiovascular, metabolic and renal conditions [25]. Additionally, in older people, barriers to prescription medications for gout can compromise gout treatment [26]. Therefore, our aim in the current study was to differentiate the prevalence of gout, both with and without comorbidity, in Taiwan aborigines and Taiwanese Han. In particular, the present study focused on the associations between comorbid diseases and comorbidity aggregations and gout in both studied ethnicities.
2. Method In this study, we extracted data for 40,672 Taiwan aborigines (86% of Paiwan and 10% of Rukai ancestry) in the Pingtung County of southern Taiwan, and 45,392 randomly selected Taiwanese Han aged 20 years or older as a comparison group from the insurance claims data of Taiwan’s Bureau of National Health Insurance (BNHI) database. Because of universal eligibility for insurance compensation in Taiwan, gout can be diagnosed with near certainty. Physician-diagnosed gout was coded using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM): 274.0 gouty arthropathy; 274.9 gout, unspecified; 274.1 gouty nephropathy; 274.10 gouty nephropathy, unspecified; 274.11 uric acid nephrolithiasis; 274.19 other gouty nephropathy; 274.8 gout with other manifestations; 274.81 gouty tophi of ear; 274.82 gouty tophi of other sites, except the ear; and 274.89 gout with other specified manifestations. Each person had one principal diagnosis of gout and up to two secondary diagnoses. All cases of gout that required care at medical service institutions from January 2004 to December 2006 were examined. We limited our analysis to gout cases that had complete follow-up data. Controls were defined as patients having gout-free status. This cross-sectional study assumed a static population. After excluding patients with incomplete data, 3906 cases of 37,482 aboriginals and 1115 cases of 37,451 Han who had gout as the principal diagnosis and comprehensive comorbidity records remained in the study. The gout-related comorbidities were: diabetes mellitus (ICD-9-CM: 250), pure hypercholesterolemia (272.0), pure hyperglyceridemia
(272.1), obesity (278), essential hypertension (401), myocardial infarction (410–412), heart failure (428), and renal insufficiency (580–589). Ethical approval for the study protocol was obtained from the institutional review board of Kaohsiung Medical University Hospital (KMUHIRB-20120031). 3. Statistical analysis Statistical analysis was performed using SAS version 9.3 software (SAS Institute Inc, Cary, NC). Generalized linear mixed models, assuming a Poisson distribution, were used to compare prevalence rates by ethnicity and by gender, stratified across age categories (20–29, 30–39, 40–49, 50–59, 60–69, and ≥ 70). Maximum likelihood prevalence ratio (PR) estimates and 95% confidence intervals (CIs) were calculated using a log-binomial model [27]. The data used a population-based cross-sectional study that had the aim of estimating the prevalence of gout, hence prevalence ratios of gout by ethnicity or comorbidity groups were estimated. Crude prevalence ratio (a simple equation) is calculated, e.g., the main effect prevalence of gout in aborigines for non-comorbidity is 4.49% and for comorbidity is 27.34%, then prevalence ratio is 6.09 (27.34%/4.49%). Descriptive statistics were calculated using a general linear regression model for continuous variables. Differences among the selected comorbid medical disorders between gout cases and gout-free cases were assessed by Pearson chi-squared and Fisher’s exact tests. Logistic regression models were used to estimate odds ratios (ORs) with 95% CIs for occurrence of gout. A stepwise binary logistic regression was conducted using an ␣level of 5% for predictor entry or removal and for delineation of the covariant comorbidities for gout risk. Interactions between ethnicity (reference, Han) and comorbidity were tested using multiple logistic regression models with an added interaction term (ethnicity × comorbidity) and the main covariates (age categories (reference, 20–29), gender and comorbid disorders). A risk score was generated for every individual by counting the number of goutassociated diseases that were present (pure hypercholesterolemia, pure hyperglyceridemia, essential hypertension, heart failure and renal insufficiency; range 0–5). A multiple logistic regression model was performed, after adjustment for age and sex, and for combined group. 4. Results The age distribution of gout prevalences and prevalence ratios between aborigines and Han are shown in Table S1 (see the Supplementary supplementary material associated with this article online, Table S1). For 2006, the prevalence of gout was higher for aborigines (men 16.45%, women 4.64%, combined 10.42%) than for Han (men 5.65%, women 0.84%, combined 2.98%), even across the six age categories (aborigines 1.59 to 26.29% and Han 0.70 to 7.20%). The prevalence ratios were higher for aborigines than for Han, regardless of gender, as shown by ratios of 2.91 for men, 5.54 for women and 3.50 combined, and regardless of age, as shown by combined group from 2.26 to 3.65. The prevalence of uric acid nephrolithiasis (ICD-9-CM 274.11) was 0.42% (95% CI = 0.36–0.50) in aborigines and 0.09% (95% CI = 0.07–0.13) in Han; the prevalence of tophi (ICD-9-CM 274.81 and 274.82) was 0.30% (95% CI = 0.25–0.36) in aborigines and 0.04% (95% CI = 0.03–0.07) in Han in 2006 (Table 1). Supplementary data, Table S2 shows the comorbidity profiles and Supplementary data, Table S3 shows the adjusted odds ratios, with ethnic- and gender-stratified modeling, for comorbidities independently associated with gout. The comorbid diseases, pure hypercholesterolemia, pure hyperglyceridemia, obesity, essential hypertension and renal insufficiency, were clearly shared by
F.-Y. Tu et al. / Joint Bone Spine 82 (2015) 45–51
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Table 1 Prevalence of gouty arthropathy, gouty nephropathy and gouty tophi according to gender and ethnicity. Gouty arthropathy
Gouty nephropathy
Gouty tophi
Gouty nephropathy and tophi aggregation
n
Prevalence % (95% CI)
n
Prevalence % (95% CI)
n
Prevalence % (95% CI)
n
Prevalence % (95% CI)
Taiwan aborigines Men Women Combined group
2455 740 3195
13.38 (12.89–13.88) 3.87 (3.60–4.15) 8.52 (8.25–8.81)
222 84 306
1.21 (1.06–1.38) 0.44 (0.35–0.54) 0.82 (0.73–0.81)
300 61 361
1.64 (1.46–1.83) 0.32 (0.25–0.41) 0.96 (0.87–1.07)
42 2 44
0.23 (0.17–0.31) 0.01 (0.003–0.04) 0.12 (0.09–0.16)
Taiwanese Han Men Women Combined group
757 125 882
64 13 77
0.38 (0.30–0.49) 0.06 (0.03–0.01) 0.21 (0.16–0.26)
116 36 152
0.70 (0.58–0.84) 0.17 (0.12–0.24) 0.41 (0.34–0.48)
4 0 4
0.01 (0.004–0.03) – 0.01 (0.004–0.03)
4.55 (4.24–4.87) 0.60 (0.50–0.72) 2.36 (2.21–2.51)
ICD-9-CM: International Classification of Diseases, Ninth Revision, Clinical Modification; CI: confidence interval. Gouty arthropathy: ICD-9-CM 274.0 (gouty arthropathy) and 274.9 (gout, unspecified). Gouty nephropathy: ICD-9-CM 274.1 (gouty nephropathy), 274.10 (gouty nephropathy, unspecified), 274.11 (uric acid nephrolithiasis) and 274.19 (other gouty nephropathy). Gouty tophi: ICD-9-CM 274.8 (gout with other manifestations), 274.81 (gouty tophi of ear), 274.82 (gouty tophi of other sites, except ear) and 274.89 (gout with other specified manifestations). The prevalence of uric acid nephrolithiasis (274.11) was 0.42% (95% CI = 0.36–0.50) in aborigines (n = 159) and 0.09% (95% CI = 0.07–0.13) in Han (n = 35) in 2006. The prevalence of tophi (274.81 and 274.82) was 0.30% (95% CI = 0.25–0.36) in aborigines (n = 3 and n = 109) and 0.04% (95% CI = 0.03–0.07) in Han (n = 0 and n = 16) in 2006.
genders of both ethnic groups. Diabetes mellitus became insignificant after adjustment for age category, gender, and other comorbid disorders, except for marginal significance in female aborigines (OR 1.23, 95% CI 1.03–1.48; Supplementary data, Table S3). Heart failure was more frequently associated with gout in aborigines (men OR = 1.83, women OR = 1.54 and combined OR = 1.72) than in Han (only combined OR = 1.46). There was no significant difference for myocardial infarction. We also showed that gout was associated with men more than women in both aboriginal men (versus women, adjusted OR = 6.79) and Han men (versus women adjusted OR = 6.73), suggesting a gender contribution (Supplementary data, Table S3). Next, to separate the influences of non-comorbidity and comorbidity profiles, Tables 2 and 3 show the age distribution of gout prevalences and prevalence ratios between aborigines and Han, stratified by comorbidity status. In gout patients without comorbidity, the prevalence was higher for aborigines (men 7.76%, women 1.08%, combined 4.49%) than for Han (men 3.21%, women 0.24%, combined 1.52%). Similarly, in gout patients with comorbidity, the prevalence was higher for aborigines (men 45.98%, women 13.33%, combined 27.34%) than for Han (men 14.85%, women 3.90%, combined 9.44%). When stratified by comorbidity status, the prevalence ratio was approximately 3.00 for aborigines compared with Han. Additionally, the prevalence ratios of gout between the non-comorbidity group and the comorbidity group for aborigines and for Han were similarly increased for gout occurrence (PR = 6.09 and 6.23), implicating comorbidity as a determinant of gout risk, specifically, in early ages (20–29 years, PR = 8.58 and 12.47; Tables 2 and 3). We next performed separate analyses for aborigines and for Han to further investigate the impact of comorbidity on gout risk in both ethnicities (Tables 4 and 5). When the analysis was stratified by comorbid condition, the comorbid disorders of pure hypercholesterolemia (6.24%, 12.58%), pure hyperglyceridemia (6.21%, 12.73%), essential hypertension (89.17%, 75.92%), and renal insufficiency (11.81%, 20.40%) were important common comorbidities of gout in aborigines and Han (adjusted OR ≥ 1.63). We found that heart failure exerts a significant effect only in aborigines (adjusted OR = 1.55) and not in Han. Because patients with gout often have multiple comorbidities, we tested whether the effects of these additional comorbidities were associated with increased gout risk. We summarized this scenario by constructing a risk score combining pure hypercholesterolemia, pure hyperglyceridemia, essential hypertension, heart failure and renal insufficiency (range 0–5; Table 6). We found that the adjusted OR for gout risk increased steadily among gout patients by score category, from 1.85 to 9.16 in
aborigines and from 1.84 to 12.90 in Han, with a per comorbidity factor increased approximately 2-fold for gout prevalence. These findings show that the presence of multiple comorbidities is an important component for gout prevalence in Taiwan.
5. Discussion In 2006, gout prevalence was 10.42% in Taiwan aborigines and 2.98% in Taiwanese Han. We showed that uric acid nephrolithiasis and tophi had prevalences of 0.42% and 0.30%, respectively, of aborigines and 0.09% and 0.04%, respectively, of Han. We noted a substantial difference in gout prevalence between ethnicities (PR = 3.50). The prevalences of gout in the non-comorbidity and comorbidity groups were 4.49% and 27.34%, respectively, in aborigines and 1.52% and 9.44%, respectively, in Han (approximate PR = 3.00). We showed that comorbidity was the most significant determinant of gout risk (overall PR = 6.09 in aborigines and 6.23 in Han), specifically at early ages (20–29 years, PR = 12.47 in aborigines and 8.58 in Han). Pure hypercholesterolemia, pure hyperglyceridemia, essential hypertension, and renal insufficiency were important comorbidities for gout in both ethnicities. The magnitude of the four comorbidity associations did not differ between men and women (Table 5). We also found that heart failure exerts a significant effect on gout risk in aborigines (adjusted OR = 1.48 in men and 1.53 in women) but not in Han. For those patients with gout and multiple comorbid diseases, gout risk increased approximately two-fold for each comorbidity factor, which helps to explain gout prevalence in Taiwan. We found that the prevalence was higher among aborigines (4.49%) than Han (1.52%) in non-comorbid gout patients. Genetic and environmental factors may contribute to gout etiology [12,28–30]. In our previously study, the aborigines had a higher alcohol use (48% versus 24% in Han) and alcohol use to be more a significant predictor of tophaceous gout risk in aborigines than Han; aborigines of gout cases with carriers of ABCG2 Q141K [T/T] had an earlier age of visit to the clinician (39 years versus 43 years in Han) [29]. A population-based study has shown a substantial heritable component for gout (35.1% in men and 17.0% in women) [12]. Recent genome-wide association studies (GWAS) have identified multiple novel genetic variants, mostly of genes involved in the renal urate-transport system, that are associated with uric acid levels and gout susceptibility [28,31]. Therefore, finding the genetic determinants, such as the renal urate-transport genes ABCG2, SLC2A9 and SLC22A12 [28], of urate homeostasis is
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F.-Y. Tu et al. / Joint Bone Spine 82 (2015) 45–51
Table 2 Prevalence of gout according non-comorbidity and comorbidity groups in Taiwan aborigines. Non-comorbidity group
Comorbidity group
Prevalence ratio (95% CI)
Gout, n
At risk population, n
Prevalence % (95% CI)
Gout, n
At risk population, n
Prevalence % (95% CI)
Men 20–29 years 30–39 years 40–49 years 50–59 years 60–69 years ≥ 70 years Overall
120 281 344 217 81 57 1100
4956 3785 3279 1451 448 258 14177
2.42 (2.03–2.9) 7.42 (6.61–8.35) 10.49 (9.44–11.66) 14.96 (13.09–17.08) 18.08 (14.54–22.48) 22.09 (17.04–28.64) 7.76 (7.31–8.23)
28 155 481 549 362 344 1919
117 431 1078 1164 731 653 4174
23.93(16.52–34.66) 35.96 (30.72–42.10) 44.62 (40.80–48.79) 47.16 (43.38–51.28) 49.52 (44.67–54.90) 52.68 (47.40–58.55) 45.98 (43.96–48.08)
Women 20–29 years 30–39 years 40–49 years 50–59 years 60–69 years ≥ 70 years Overall
4 17 45 32 19 30 147
4970 3585 3010 1198 443 373 13579
0.08 (0.03–0.21) 0.47 (0.29–0.76) 1.50 (1.12–2.00) 2.67 (1.89–3.78) 4.29 (2.74–6.72) 8.04 (5.62–11.50) 1.08 (0.92–1.27)
10 21 103 179 172 255 740
127 349 1213 1466 1072 1325 5552
7.87 (4.24–14.64) 6.02 (3.92–9.23) 8.49 (7.00–10.30) 12.21 (10.55–14.14) 16.04 (13.82–18.63) 19.25 (17.02–21.76) 13.33 (12.40–14.32)
97.83 (30.68–311.94) 12.69 (6.69–24.05) 5.68 (4.00–8.06) 4.57 (3.14–6.66) 3.74 (2.33–6.01) 2.39 (1.64–3.49) 12.31 (10.32–14.70)
124 298 389 249 100 87 1247
9926 7370 6289 2649 891 631 27756
1.25 (1.05–1.49) 4.04 (3.61–4.53) 6.19 (5.60–6.83) 9.40 (8.30–10.64) 11.22 (9.23–13.65) 13.79 (11.17–17.01) 4.49 (4.25–4.75)
38 176 584 728 534 599 2659
244 780 2291 2630 1803 1978 9726
15.57 (11.33–21.40) 22.56 (19.46–26.16) 25.49 (23.51–27.64) 27.68 (25.74–29.77) 29.62 (27.21–32.24) 30.28 (27.95–32.81) 27.34 (26.32–28.40)
12.47 (8.67–17.93) 5.58 (4.63–6.72) 4.12 (3.63–4.69) 2.94 (2.55–3.40) 2.64 (2.13–3.27) 2.20 (1.75–2.75) 6.09 (5.69–6.51)
Combined group 20–29 years 30–39 years 40–49 years 50–59 years 60–69 years ≥ 70 years Overall
9.88 (6.55–14.91) 4.84 (3.98–5.89) 4.25 (3.70–4.88) 3.15 (2.70–3.69) 2.74 (2.15–3.49) 2.38 (1.80–3.16) 5.93 (5.50–6.38)
Prevalence ratio with 95% confidence interval (CI) was estimated by the log-binomial model.
important because elevated serum uric acid levels, the formation of urate microcrystals and the attraction and activation of susceptible phagocytes are important. Patients with gout often have multiple comorbidities, and there is an increasing body of evidence showing that hyperuricemia is associated with hypertension, heart failure, and chronic kidney disease [25]. Moreover, about 64.5% of hyperuricemic children and adolescents are obesity [32]; a relatively high proportion of Taiwanese hyperuricemic children and adolescents are affected by hypercholesterolemia and hyperglyceridemia, 67.9% and 61.8%,
respectively [23], and 50–70% of hyperglyceridemic patients have gout, indicating that hyperglyceridemia is an important serum urate determinant [33]. Between the two coexisting illnesses, we observed that hyperglyceridemia was a stronger independent comorbid factor for gout risk than hypercholesterolemia in both ethnic groups (OR ≥ 2.57 versus OR ≥ 1.89). Hypertriglyceridemia is an independent risk factor in men on gout development with and without hyperuricemia (hazard ratios 1.38 and 1.40) [34]. Furthermore, hypertension was an independent risk factor for gout after adjusting for diuretics [24], and 17.5–59.7% of hypertensive
Table 3 Prevalence of gout in non-comorbidity and comorbidity groups in Taiwanese Han. Non-comorbidity group
Comorbidity group
Prevalence ratio (95% CI)
Gout, n
At risk population, n
Prevalence % (95% CI)
Gout, n
At risk population, n
Prevalence % (95% CI)
Men 20–29 years 30–39 years 40–49 years 50–59 years 60–69 years ≥ 70 years Overall
43 168 112 67 23 9 422
2987 5438 2786 1243 484 217 13,155
1.44 (1.07–1.94) 3.09 (2.66–3.59) 4.02 (3.34–4.84) 5.39 (4.24–6.85) 4.75 (3.16–7.15) 4.15 (2.16–7.97) 3.21 (2.92–3.53)
14 65 148 139 87 66 519
105 549 853 882 627 479 3495
13.33 (7.90–22.52) 11.84 (9.28–15.10) 17.35 (14.77–20.38) 15.76 (13.35–18.61) 13.88 (11.25–17.12) 13.78 (10.82–17.54) 14.85 (13.63–16.18)
Women 20–29 years 30–39 years 40–49 years 50–59 years 60–69 years ≥ 70 years Overall
6 10 9 7 5 4 41
5782 6632 2923 1404 390 258 17,389
0.10 (0.05–0.23) 0.15 (0.08–0.28) 0.31 (0.16–0.59) 0.50 (0.24–1.05) 1.28 (0.53–3.08) 1.55 (0.58–4.13) 0.24 (0.17–0.32)
1 3 20 40 27 42 133
208 426 581 898 572 727 3412
0.48 (0.07–3.42) 0.70 (0.23–2.18) 3.44 (2.22–5.34) 4.45 (3.27–6.07) 4.72 (3.24–6.88) 5.78 (4.27–7.82) 3.90 (3.29–4.62)
4.63 (0.56–38.48) 4.67 (1.29–16.97) 11.18 (5.09–24.55) 8.93 (4.00–19.94) 3.68 (1.42–9.56) 3.73 (1.34–10.39) 16.53 (11.65–23.46)
Combined group 49 20–29 years 178 30–39 years 40–49 years 121 74 50–59 years 28 60–69 years 13 ≥ 70 years 463 Overall
8769 12,070 5709 2647 874 475 30,544
0.56 (0.42–0.74) 1.48 (1.27–1.71) 2.12 (1.77–2.53) 2.80 (2.23–3.51) 3.20 (2.21–4.64) 2.74 (1.59–4.71) 1.52 (1.38–1.66)
15 68 168 179 114 108 652
313 975 1434 1780 1199 1206 6907
4.79 (2.89–7.95) 6.97 (5.50–8.85) 11.72 (10.07–13.63) 10.06 (8.69–11.64) 9.51 (7.91–11.42) 8.96 (7.42–10.81) 9.44 (8.74–10.19)
8.58 (4.81–15.29) 4.73 (3.58–6.25) 5.53 (4.38–6.98) 3.60 (2.74–4.72) 2.97 (1.96–4.49) 3.27 (1.84–5.82) 6.23 (5.53–7.02)
Prevalence ratio with 95% confidence interval (CI) was estimated by the log-binomial model.
9.26 (5.07–16.93) 3.83 (2.88–5.10) 4.32 (3.38–5.52) 2.92 (2.18–3.91) 2.92 (1.84–4.62) 3.32 (1.66–6.67) 4.63 (4.07–5.26)
Table 4 Association between comorbidity and gout in comorbidity group. Men
Crude OR (95% CI)
Women
Crude OR (95% CI)
Combined group
Crude OR (95% CI)
Controls
Gout cases
Controls
Gout cases
Controls
1919 55.79 (12.99)
2255 52.83 (13.87)
1.02 (1.01–1.02)
740 62.27 (13.33)
4812 57.10 (14.24)
1.03 (1.02–1.03)
431 (22.46) 106 (5.52) 122 (6.36) 27 (1.41) 1693 (88.22) 57 (2.97) 158 (8.23) 232 (12.09)
662 (29.36) 74 (3.28) 82 (3.64) 28 (1.24) 1824 (80.89) 54 (2.39) 117 (5.19) 168 (7.45)
0.70 (0.61–0.80) 1.72 (1.27–2.33) 1.80 (1.35–2.40) 1.14 (0.67–1.93) 1.77 (1.49–2.11) 1.25(0.86–1.82) 1.64 (1.28–2.10) 1.71 (1.39–2.11)
218 (29.46) 60 (8.11) 43 (5.81) 14 (1.89) 678 (91.62) 26 (3.51) 112 (15.14) 82 (11.08)
1219 (25.33) 250 (5.20) 118 (2.45) 111 (2.31) 4088 (84.95) 119 (2.47) 439 (9.12) 322 (6.69)
1.23 (1.04–1.46) 1.61 (1.20–2.16) 2.45 (1.72–3.51) 0.82 (0.47–1.43) 1.94 (1.48–2.54) 1.44 (0.93–2.21) 1.78 (1.42–2.22) 1.74 (1.35–2.24)
2659 57.59 (13.40) 1919 (72.17) 649 (24.41) 166 (6.24) 165 (6.21) 41 (1.54) 2371 (89.17) 83 (3.12) 270 (10.15) 314 (11.81)
7067 55.74 (14.26) 2255 (31.91) 1881 (26.62) 324 (4.58) 200 (2.83) 139 (1.97) 5912 (83.66) 173 (2.45) 556 (7.87) 490 (6.93)
1.01 (1.01–1.01) 5.53 (5.02–6.11) 0.89 (0.80–0.99) 1.39 (1.14–1.68) 2.27 (1.84–2.81) 0.78 (0.55–1.11) 1.61 (1.40–1.85) 1.28 (0.99–1.68) 1.32 (1.14–1.54) 1.80 (1.55–2.09)
Taiwanese Han, n Age (SD), years Men, n (%) Diabetes mellitus, n (%) Pure hypercholesterolemia, n (%) Pure hyperglyceridemia, n (%) Obesity, n (%) Essential hypertension, n (%) Myocardial infarction, n (%) Heart failure, n (%) Renal insufficiency, n (%)
519 52.80 (13.05)
2976 52.97 (13.91)
1.00(0.99–1.01)
133 61.56 (13.14)
3279 54.89 (15.92)
1.03 (1.02–1.04)
141 (27.17) 60 (11.56) 62 (11.95) 10 (1.93) 385 (74.18) 24 (4.62) 33 (6.36) 104 (20.04)
1051 (35.32) 227 (7.63) 178 (5.98) 38 (1.28) 2037 (68.45) 125 (4.20) 150 (5.04) 353 (11.86)
0.68 (0.56–0.84) 1.58 (1.17–2.14) 2.13(1.57–2.90) 1.52 (0.75–3.07) 1.32 (1.07–1.64) 1.11 (0.71–1.73) 1.28 (0.87–1.89) 1.86 (1.46–2.37)
50 (37.59) 22 (16.54) 21 (15.79) 4 (3.01) 110 (82.71) 5 (3.76) 15 (11.28) 29 (21.80)
1101 (33.58) 306 (9.33) 142 (4.33) 153 (4.67) 2200 (67.09) 91 (2.78) 214 (6.53) 469 (14.30)
1.19 (0.83–1.71) 1.93 (1.20–3.09) 4.14 (2.52–6.80) 0.63 (0.23–1.74) 2.35 (1.49–3.70) 1.37 (0.55–3.43) 1.82 (1.05–3.17) 1.67 (1.09–2.55)
652 54.59 (13.53) 519 (79.60) 191 (29.29) 82 (12.58) 83 (12.73) 14 (2.15) 495 (75.92) 29 (4.45) 48 (7.36) 133 (20.40)
6255 53.98 (15.03) 2976 (47.58) 2152 (34.40) 533 (8.52) 320 (5.12) 191 (3.05) 4237 (67.74) 216 (3.45) 364 (5.82) 822 (13.14)
1.00 (0.99–1.01) 4.30 (3.53–5.24) 0.79 (0.66–0.94) 1.54 (1.21–1.98) 2.71 (2.10–3.50) 0.70 (0.40–1.21) 1.50 (1.25–1.81) 1.30 (0.88–1.94) 1.29 (0.94–1.76) 1.69 (1.38–2.08)
F.-Y. Tu et al. / Joint Bone Spine 82 (2015) 45–51
Gout cases Taiwan aborigines, n Age (SD), years Men, n (%) Diabetes mellitus, n (%) Pure hypercholesterolemia, n (%) Pure hyperglyceridemia, n (%) Obesity, n (%) Essential hypertension, n (%) Myocardial infarction, n (%) Heart failure, n (%) Renal insufficiency, n (%)
Crude odds ratio (OR) with 95% confidence interval (CI) in parentheses was estimated according to gender and ethnicity using a logistic regression model.
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Table 5 Multivariate odds ratios of comorbid factors for gout risk in comorbidity group. Taiwan aborigines
Age, years Men Diabetes mellitus Pure hypercholesterolemia Pure hyperglyceridemia Obesity Essential hypertension Myocardial infarction Heart failure Renal insufficiency
Taiwanese Han
Men
Women
Combined group
Men
Women
Combined group
Adjusted OR (95% CI)
Adjusted OR (95% CI)
Adjusted OR (95% CI)
Adjusted OR (95% CI)
Adjusted OR (95% CI)
Adjusted OR (95% CI)
1.01 (1.01–1.02)
1.02 (1.02–1.03)
–
1.02 (1.01–1.03)
0.76 (0.65–0.88) 1.80 (1.31–2.47) 2.24 (1.66–3.04) – 1.81 (1.48–2.20) – 1.48 (1.14–1.92) 1.94 (1.55–2.41)
– 1.55 (1.14–2.11) 3.28 (2.25–4.79) – 2.02 (1.51–2.69) – 1.53 (1.21–1.94) 2.06 (1.57–2.71)
1.02 (1.01–1.02) 6.27 (5.65–6.95) – 1.63 (1.31–2.03) 2.57 (2.02–3.28) – 2.00 (1.71–2.34) – 1.55 (1.30–1.84) 2.00 (1.68–2.37)
0.76 (0.61–0.94) 1.82 (1.34–2.48) 2.59 (1.89–3.55) – 1.60 (1.27–2.01) – – 2.21 (1.72–2.86)
– 1.85 (1.12–3.05) 4.62 (2.74–7.80) – 2.55 (1.56–4.19) – – 2.36 (1.51–3.69)
– 4.38 (3.59–5.35) – 1.89 (1.46–2.46) 3.02 (2.30–3.96) – 1.96 (1.61–2.40) – – 2.33 (1.87–2.90)
Adjusted odds ratios (OR) with 95% confidence intervals (CI) in parentheses were estimated according to gender and ethnicity using a stepwise multiple logistic regression model; only significant variables were entered to this model (P < 0.05) otherwise indicated by ‘–’.
Caucasians are estimated to have gout [10,35]. We found that the independent effect of hypertension for both ethnic groups (OR = 4.53 and OR = 4.24) was most evident in the general population of aborigines compared with Han (60.70% and 44.39%). Similarly, the consistency of results for this comorbid condition supports the presence, among general populations, of an association between hypertension and gout (89.17% and 75.92%; OR ≥ 1.96). Additionally, we found that heart failure exerts a significant effect on gout risk only in aborigines. A related issue is that heart disease occurrence is rising in developed countries and is linked to serum uric acid levels [18]. In this study, heart failure was independently linked to gout risk in the general populations (aborigines OR = 1.72; Han OR = 1.46), but this association was more significant in aborigines than in Han (P for interaction = 0.0067). The association between heart failure and gout was consistent among subjects in the comorbid condition group. Interestingly, we found similar proportions of gouty nephropathy and uric acid nephrolithiasis (ICD-9-CM: 274.10–274.19) in aborigines 8.96% (350/3906) and in Han 7.26% (81/1115; Table 1). This suggests that the sequelae of chronic gout may include crystal deposition in the kidneys that could predispose patients to arteriosclerosis and interstitial fibrosis [1–3]. Renal impairment is a significant risk factor for gout [5]. Advanced arteriolosclerosis, glomerulosclerosis and interstitial fibrosis are associated with urate crystal aggregates in the outer medulla [18]. The independent effect of renal insufficiency on gout risk was significant in both ethnic groups, both in the general populations and in the subjects with comorbid conditions (OR = 2.69 and OR = 3.11; OR = 2.00 and OR = 2.23). However, because the daily turnover of uric acid includes two-thirds clearance through urinary excretion and one-third clearance by the gut [1], renal insufficiency is likely to disrupt this physiological process. Together, these findings for the five coexistent illnesses suggest additional reasons for
the lower background incidence of gout that go beyond the lower baseline serum uric acid levels. Obesity and insulin resistance correlate with gout [36]. A retrospective analysis in the UK found that obesity is most associated with gout [10]. Although less than 3% of aborigines and Han with gout were obese compared to 27.7% in the UK study, obesity was still independently associated with risk of gout in patients from both ethnic groups (OR ≥ 2.19). In the present study, there was a similar concordance with diabetes, 16.62% in aborigines and 17.13% in Han, but lower than the co-occurrences of gout and diabetes reported for Germany, 25.9%, and the US, 19.9% [10,35]. The subjects with comorbidities had a higher frequency of diabetes among goutfree controls (26.62 and 34.40% in aborigines and Han) than among gout patients (24.41% and 29.29), which could explain the low association with gout in this data set. However, the co-occurrences of gout and diabetes still had a higher frequency in both ethnicities. Furthermore, from the NHANES data, mortality due to myocardial infarction is 1.77-fold in men and 3.00-fold in women after comparing the highest and lowest quartiles for serum urate [19]. In MRFIT, a relationship between gout and the risk of acute myocardial infarction was evident among those with and without hyperuricemia [37]. In a cohort study from the Taiwan National Health Insurance Database, a risk of myocardial infarction was demonstrated among those with and without gout [38]. However, we failed to observe a relationship between gout and myocardial infarction in this cross-sectional data set. There are several limitations to be noted regarding this study. The BNHI is primarily a health insurance database that contains limited information on criteria for clinical diagnosis (e.g., urate crystals in joint fluid in gout patients, uric acid levels) and on environmental factors (e.g., lifestyle habits, alcohol use) [12]. Poor validation of medical record ICD-9 diagnoses of gout in a veterans
Table 6 Comorbidity aggregations in gout patients in comorbidity group. Taiwan aborigines
Gout cases Risk score 120 (4.51) 0 1 1921 (72.25) 505 (18.99) 2 97 (3.65) 3 16 (0.60) 4
Adjusted OR (95% CI)
Controls 620 (8.77) 5512 (78.00) 846 (11.97) 78 (1.10) 11 (0.16)
1.00 1.85 (1.49–2.29) 3.47 (2.72–4.42) 6.92 (4.68–10.21) 9.16 (3.87–21.70)
Taiwanese Han
Gout cases
Controls
52 (7.98) 406 (62.27) 151 (23.16) 39 (5.98) 4 (0.61)
1008 (16.12) 4357 (69.66) 759 (12.13) 123 (1.97) 8 (0.13)
Adjusted OR (95% CI)
1.00 1.84 (1.36–2.49) 3.97 (2.83–5.58) 7.56 (4.68–12.20) 12.90 (3.48–47.85)
Combined group
Gout cases
Controls
172 (5.19) 2327 (70.28) 656 (19.81) 136 (4.11) 20 (0.60)
1628 (12.22) 9869 (74.08) 1605 (12.05) 201 (1.51) 19 (0.14)
Adjusted OR (95% CI)
1.00 1.85 (1.55–2.20) 3.58 (2.94–4.36) 7.03 (5.20–9.51) 10.08 (4.85–20.93)
A risk score was generated for every individual by counting the disease status associated with gout (pure hypercholesterolemia, pure hyperglyceridemia, essential hypertension, heart failure and renal insufficiency; range 0–5). The comorbidity aggregations of score = 5 was no found in this data set. Adjusted ORs were adjusted for age and sex, and for combined group, the ethnicity using a multiple logistic regression model.
F.-Y. Tu et al. / Joint Bone Spine 82 (2015) 45–51
affairs database is seen [39]. However, the utility and validity of gout diagnoses in claims databases have been assessed and have been shown to be reasonably robust [40]. In addition, our estimate of gout prevalence is similar to that reported in some studies in Taiwan (11.7% in aborigines; 3.0% in Han) [16,17]. In conclusion, we have observed a substantial risk of gout with comorbid diseases, specifically in early age, in Taiwan aborigines and Taiwanese Han. In gout patients without comorbidity, the prevalence of gout was higher among aborigines than Han, suggesting that genetic and environmental factors contribute to gout etiology. Therefore, primary prevention of gout should prompt evaluation for potentially modifiable risk factors (e.g., gout susceptibility genes and dietary habits) and important associated coexisting illness (e.g., pure hypercholesterolemia, pure hyperglyceridemia, essential hypertension, renal insufficiency and heart failure) that may require intervention. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgements We thank the Bureau National Health Insurance for supplying the data. Funding: This works was supported by Kaohsiung Medical University [KMU-M103018] and [KMUH99-9R17]. Appendix A. Supplementary data Supplementary data (Tables S1–S3) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.jbspin.2014.07.002. References [1] Richette P, Bardin T. Gout. Lancet 2010;375:318–28. [2] Terkeltaub RA. Clinical practice. Gout. N Engl J Med 2003;349:1647–55. [3] Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann Intern Med 2005;143:499–516. [4] 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. [5] Roddy E, Zhang W, Doherty M. The changing epidemiology of gout. Nat Clin Pract Rheumatol 2007;3:443–9. [6] Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum 2008;58:26–35. [7] Adams JU. New relief for gout. Nat Biotechnol 2009;27:309–11. [8] Yu KH, See LC, Kuo CF, et al. Prevalence and incidence in patients with autoimmune rheumatic diseases: a nationwide population-based study in Taiwan. Arthritis Care Res (Hoboken) 2013;65:244–50. [9] Harris CM, Lloyd DC, Lewis J. The prevalence and prophylaxis of gout in England. J Clin Epidemiol 1995;48:1153–8. [10] Annemans L, Spaepen E, Gaskin M, et al. Gout in the UK and Germany: prevalence, comorbidities and management in general practice 2000–2005. Ann Rheum Dis 2008;67:960–6. [11] Kuo CF, Grainge MJ, Mallen C, et al. Rising burden of gout in the UK but continuing suboptimal management: a nationwide population study. Ann Rheum Dis 2014, doi:10.1136/annrheumdis-2013-204463.
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[12] Kuo CF, Grainge MJ, See LC, et al. Familial aggregation of gout and relative genetic and environmental contributions: a nationwide population study in Taiwan. Ann Rheum Dis 2013, doi:10.1136/annrheumdis-2013-204067. [13] Miao Z, Li C, Chen Y, et al. Dietary and lifestyle changes associated with high prevalence of hyperuricemia and gout in the Shandong coastal cities of Eastern China. J Rheumatol 2008;35:1859–64. [14] Nan H, Qiao Q, Dong Y, et al. The prevalence of hyperuricemia in a population of the coastal city of Qingdao, China. J Rheumatol 2006;33:1346–50. [15] Klemp P, Stansfield SA, Castle B, et al. Gout is on the increase in New Zealand. Ann Rheum Dis 1997;56:22–6. [16] Chang SJ, Ko YC, Wang TN, et al. High prevalence of gout and related risk factors in Taiwan’s Aborigines. J Rheumatol 1997;24:1364–9. [17] Chou CT, Lai JS. The epidemiology of hyperuricaemia and gout in Taiwan aborigines. Br J Rheumatol 1998;37:258–62. [18] Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med 2008;359:1811–21. [19] Saag KG, Choi H. Epidemiology, risk factors, and lifestyle modifications for gout. Arthritis Res Ther 2006;8:S2. [20] Edwards NL. The role of hyperuricemia and gout in kidney and cardiovascular disease. Cleve Clin J Med 2008;75:S13–6. [21] Bhole V, Choi JW, Kim SW, et al. Serum uric acid levels and the risk of type 2 diabetes: a prospective study. Am J Med 2010;123:957–61. [22] Choi HK, De Vera MA, Krishnan E. Gout and the risk of type 2 diabetes among men with a high cardiovascular risk profile Rheumatology (Oxford) 2008;47:1567–70. [23] Ko YC, Huang MC, Wang TN, et al. Prevalence and risk factors associated with dyslipidaemia in children and adolescents among ethnic groups in Taiwan. Public Health 2005;119:489–97. [24] Choi HK, Atkinson K, Karlson EW, et al. Obesity, weight change, hypertension, diuretic use, and risk of gout in men: the health professionals follow-up study. Arch Intern Med 2005;165:742–8. [25] Bakris GL, Doghramji PP, Keenan RT, et al. Casebook challenges: managing gout, hyperuricemia and comorbidities – dialogue with the experts. Am J Med 2014;127:S1. [26] Hoskison KT, Wortmann RL. Management of gout in older adults: barriers to optimal control. Drugs Aging 2007;24:21–36. [27] Spiegelman D, Hertzmark E. Easy SAS calculations for risk or prevalence ratios and differences. Am J Epidemiol 2005;162:199–200. [28] Reginato AM, Mount DB, Yang I, et al. The genetics of hyperuricaemia and gout. Nat Rev Rheumatol 2012;8:610–21. [29] Tu HP, Ko AM, Chiang SL, et al. Joint effects of alcohol consumption and ABCG2 Q141K on chronic tophaceous gout risk. J Rheumatol 2014;41:749– 58. [30] Cheng LS, Chiang SL, Tu HP, et al. Genomewide scan for gout in Taiwanese aborigines reveals linkage to chromosome 4q25. Am J Hum Genet 2004;75:498–503. [31] Merriman TR, Dalbeth N. The genetic basis of hyperuricaemia and gout. Joint Bone Spine 2011;78:35–40. [32] Ko YC, Wang TN, Tsai LY, et al. High prevalence of hyperuricemia in adolescent Taiwan aborigines. J Rheumatol 2002;29:837–42. [33] Becker MA, Jolly M. Hyperuricemia and associated diseases. Rheum Dis Clin North Am 2006;32:275–93 [v-vi]. [34] Chen JH, Pan WH, Hsu CC, et al. Impact of obesity and hypertriglyceridemia on gout development with or without hyperuricemia: a prospective study. Arthritis Care Res (Hoboken) 2013;65:133–40. [35] Riedel AA, Nelson M, Wallace K, et al. Prevalence of comorbid conditions and prescription medication use among patients with gout and hyperuricemia in a managed care setting. J Clin Rheumatol 2004;10:308–14. [36] Setty AR, Curhan G, Choi HK. Obesity, waist circumference, weight change, and the risk of psoriasis in women: Nurses’ Health Study II. Arch Intern Med 2007;167:1670–5. [37] Krishnan E, Baker JF, Furst DE, et al. Gout and the risk of acute myocardial infarction. Arthritis Rheum 2006;54:2688–96. [38] Kuo CF, See LC, Yu KH, et al. Significance of serum uric acid levels on the risk of all-cause and cardiovascular mortality. Rheumatology (Oxford) 2013;52:127–34. [39] Malik A, Dinnella JE, Kwoh CK, et al. Poor validation of medical record ICD-9 diagnoses of gout in a veterans affairs database. J Rheumatol 2009;36:1283– 6. [40] Kuo CF, Yu KH, See LC, et al. Risk of myocardial infarction among patients with gout: a nationwide population-based study Rheumatology (Oxford) 2013;52:111–7.
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Original article
Prevalence of gout with comorbidity aggregations in southern Taiwan Fang-Yi Tu a,1 , Gau-Tyan Lin b,c,d,1 , Su-Shin Lee e,f , Yi-Ching Tung g , Hung-Ping Tu g,∗,2 , Hung-Che Chiang h,i,2 a
Public Health Bureau, Pingtung County Government, Pingtung, Taiwan Department of Orthopedic Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan Kaohsiung Municipal United Hospital, Kaohsiung, Taiwan d Graduate Institute of Medicine, College of Medicine, Kaohsiung, Taiwan e Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan f Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan g Department of Public Health and Environmental Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung, Taiwan h Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Miaoli, Taiwan i Department of Occupational Medicine, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan b c
a r t i c l e
i n f o
Article history: Accepted 1st July 2014 Available online 17 September 2014 Keywords: Gout Comorbidity Prevalence Comorbidity aggregations
a b s t r a c t Objective: Comorbidity is an important concern for chronic gout patients. We evaluated the relationship between comorbidity profiles and gout in Taiwan aborigines and Taiwanese Han. Methods: We used the claims data from the Taiwan national health insurance database for 2004 to 2006. Physician-diagnosed gout and comorbidities were coded using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Total sampling from Pingtung County of southern Taiwan included 37,482 aborigines (gout cases, n = 3906 and controls, n = 33,576) and 37,451 Han (gout cases, n = 1115 and controls, n = 36,336). Results: In 2006, the gout prevalences were 10.42% and 2.98% (prevalence ratio [PR] = 3.50) in the aborigines and Han general populations, respectively. The prevalences of uric acid nephrolithiasis and tophi were higher in aborigines (0.42% and 0.30%, respectively) than in Han (0.09% and 0.04%, respectively). When stratified by comorbidity status, the prevalences of gout were 4.49% and 27.34% in aborigines and 1.52% and 9.44% in Han (approximate PR = 3.00). Similarly, the prevalence ratios of gout in the comorbidity group, compared with the non-comorbidity group, were 6.09 in aborigines and 6.23 in Han. Multivariate odds ratios [ORs] showed that hypercholesterolemia, hyperglyceridemia, essential hypertension and renal insufficiency were the common comorbidities of gout (OR ≥ 1.63); heart failure exerted a significant effect only in aborigines (OR = 1.55). For five comorbidity factors, patients with multiple comorbidities had higher gout prevalence (maximum OR = 12.90). Conclusion: Gout prevalence was higher in aborigines, both with and without comorbidities, than in Han. The comorbid diseases and comorbidity aggregations showed a substantial association with gout occurrence in both ethnicities. © 2014 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction Gout is characterized by monosodium urate deposits in the soft tissues of hyperuricemic patients [1]. Clinical symptoms involve recurrent flares of acute arthritis, chronic arthropathy, tophi, uric acid urolithiasis, and renal impairment [1,2]. The affected joints
∗ Corresponding author. Tel.: +886 7 31 21 101; fax: +886 7 322 75 08. E-mail address: [email protected] (H.-P. Tu). 1 These 2 authors contributed equally to this work. 2 These 2 authors contributed equally to this work.
often undergo cartilage degeneration, marginal bone erosion, and synovial proliferation [1–3]. Acute flares of gouty arthritis are disabling, excruciating, and sudden. These flares produce burning pain, swelling, redness, warmth, and stiffness in the affected joint and require rapid, effective, and safe treatments [2,3]. Gout is the most prevalent inflammatory arthritis in developed countries [4]. Gout also occurs in rapidly westernized populations, in particular, among indigenous groups or migrants from rural to urban communities [5]. Epidemiologic data indicate that the prevalence of gout is rising and is greater than that of rheumatoid disease in men over 40 years of age in the US [6]. In addition to a higher incidence of gout, patient care has evolved over the past 20 years [7]. In
http://dx.doi.org/10.1016/j.jbspin.2014.07.002 1297-319X/© 2014 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
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F.-Y. Tu et al. / Joint Bone Spine 82 (2015) 45–51
the Taiwan general population from 2000 to 2008, the prevalence of rheumatoid arthritis was 52.4 per 100,000 persons, and the incidence was 17.3 per 100,000 person-years [8]. A multicenter study of UK general practices showed a 3-fold rise in gout occurrence between the 1970s and the 1990s (from 0.03 to 0.095%) [9] and a 1.4% rise from 2000 to 2005 compared to IMS databases from Germany and UK [10]. A US National Health and Nutrition Examination Survey [NHANES] showed that the prevalence of gout among adults was 3.9% in 2007–2008 [4]. In the UK general population from 1997 to 2012, the prevalence of gout was 2.49% and the incidence of gout was 1.77 per 1000 person-years, with a 63.9% increase in prevalence and a 29.6% increase in incidence [11]. In Taiwan, the gout prevalence was 4.62% in 2004 from the National Health Insurance (NHI) database [12]. In Mainland China, the gout prevalence had risen to 1.14% in 2004 from 0.36% in 2002 [13,14]. Among Polynesian peoples, such as the New Zealand Maoris, the prevalences of hyperuricemia and gout are 27.1% and 13.9%, respectively, in men and 26.6% and 2%, respectively, in women [15]. In highland Taiwan aborigines, the presence of hyperuricemia can be as high as 41–82% and the prevalence of gout as high as 2–20% [16,17]. Associations between gout and hypertension, diabetes, kidney disease, and cardiovascular disease have been observed since the late 19th century [18]. Gout is frequently associated with older age [19]. In aging populations, patients tend to be sicker and to have more comorbid illness, including diabetes mellitus, heart failure, hypertension, hypercholesterolemia, hyperglyceridemia, obesity and chronic kidney disease [1,20–24]. Clinical strategies for the management of gout must include consideration of these and other common cardiovascular, metabolic and renal conditions [25]. Additionally, in older people, barriers to prescription medications for gout can compromise gout treatment [26]. Therefore, our aim in the current study was to differentiate the prevalence of gout, both with and without comorbidity, in Taiwan aborigines and Taiwanese Han. In particular, the present study focused on the associations between comorbid diseases and comorbidity aggregations and gout in both studied ethnicities.
2. Method In this study, we extracted data for 40,672 Taiwan aborigines (86% of Paiwan and 10% of Rukai ancestry) in the Pingtung County of southern Taiwan, and 45,392 randomly selected Taiwanese Han aged 20 years or older as a comparison group from the insurance claims data of Taiwan’s Bureau of National Health Insurance (BNHI) database. Because of universal eligibility for insurance compensation in Taiwan, gout can be diagnosed with near certainty. Physician-diagnosed gout was coded using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM): 274.0 gouty arthropathy; 274.9 gout, unspecified; 274.1 gouty nephropathy; 274.10 gouty nephropathy, unspecified; 274.11 uric acid nephrolithiasis; 274.19 other gouty nephropathy; 274.8 gout with other manifestations; 274.81 gouty tophi of ear; 274.82 gouty tophi of other sites, except the ear; and 274.89 gout with other specified manifestations. Each person had one principal diagnosis of gout and up to two secondary diagnoses. All cases of gout that required care at medical service institutions from January 2004 to December 2006 were examined. We limited our analysis to gout cases that had complete follow-up data. Controls were defined as patients having gout-free status. This cross-sectional study assumed a static population. After excluding patients with incomplete data, 3906 cases of 37,482 aboriginals and 1115 cases of 37,451 Han who had gout as the principal diagnosis and comprehensive comorbidity records remained in the study. The gout-related comorbidities were: diabetes mellitus (ICD-9-CM: 250), pure hypercholesterolemia (272.0), pure hyperglyceridemia
(272.1), obesity (278), essential hypertension (401), myocardial infarction (410–412), heart failure (428), and renal insufficiency (580–589). Ethical approval for the study protocol was obtained from the institutional review board of Kaohsiung Medical University Hospital (KMUHIRB-20120031). 3. Statistical analysis Statistical analysis was performed using SAS version 9.3 software (SAS Institute Inc, Cary, NC). Generalized linear mixed models, assuming a Poisson distribution, were used to compare prevalence rates by ethnicity and by gender, stratified across age categories (20–29, 30–39, 40–49, 50–59, 60–69, and ≥ 70). Maximum likelihood prevalence ratio (PR) estimates and 95% confidence intervals (CIs) were calculated using a log-binomial model [27]. The data used a population-based cross-sectional study that had the aim of estimating the prevalence of gout, hence prevalence ratios of gout by ethnicity or comorbidity groups were estimated. Crude prevalence ratio (a simple equation) is calculated, e.g., the main effect prevalence of gout in aborigines for non-comorbidity is 4.49% and for comorbidity is 27.34%, then prevalence ratio is 6.09 (27.34%/4.49%). Descriptive statistics were calculated using a general linear regression model for continuous variables. Differences among the selected comorbid medical disorders between gout cases and gout-free cases were assessed by Pearson chi-squared and Fisher’s exact tests. Logistic regression models were used to estimate odds ratios (ORs) with 95% CIs for occurrence of gout. A stepwise binary logistic regression was conducted using an ␣level of 5% for predictor entry or removal and for delineation of the covariant comorbidities for gout risk. Interactions between ethnicity (reference, Han) and comorbidity were tested using multiple logistic regression models with an added interaction term (ethnicity × comorbidity) and the main covariates (age categories (reference, 20–29), gender and comorbid disorders). A risk score was generated for every individual by counting the number of goutassociated diseases that were present (pure hypercholesterolemia, pure hyperglyceridemia, essential hypertension, heart failure and renal insufficiency; range 0–5). A multiple logistic regression model was performed, after adjustment for age and sex, and for combined group. 4. Results The age distribution of gout prevalences and prevalence ratios between aborigines and Han are shown in Table S1 (see the Supplementary supplementary material associated with this article online, Table S1). For 2006, the prevalence of gout was higher for aborigines (men 16.45%, women 4.64%, combined 10.42%) than for Han (men 5.65%, women 0.84%, combined 2.98%), even across the six age categories (aborigines 1.59 to 26.29% and Han 0.70 to 7.20%). The prevalence ratios were higher for aborigines than for Han, regardless of gender, as shown by ratios of 2.91 for men, 5.54 for women and 3.50 combined, and regardless of age, as shown by combined group from 2.26 to 3.65. The prevalence of uric acid nephrolithiasis (ICD-9-CM 274.11) was 0.42% (95% CI = 0.36–0.50) in aborigines and 0.09% (95% CI = 0.07–0.13) in Han; the prevalence of tophi (ICD-9-CM 274.81 and 274.82) was 0.30% (95% CI = 0.25–0.36) in aborigines and 0.04% (95% CI = 0.03–0.07) in Han in 2006 (Table 1). Supplementary data, Table S2 shows the comorbidity profiles and Supplementary data, Table S3 shows the adjusted odds ratios, with ethnic- and gender-stratified modeling, for comorbidities independently associated with gout. The comorbid diseases, pure hypercholesterolemia, pure hyperglyceridemia, obesity, essential hypertension and renal insufficiency, were clearly shared by
F.-Y. Tu et al. / Joint Bone Spine 82 (2015) 45–51
47
Table 1 Prevalence of gouty arthropathy, gouty nephropathy and gouty tophi according to gender and ethnicity. Gouty arthropathy
Gouty nephropathy
Gouty tophi
Gouty nephropathy and tophi aggregation
n
Prevalence % (95% CI)
n
Prevalence % (95% CI)
n
Prevalence % (95% CI)
n
Prevalence % (95% CI)
Taiwan aborigines Men Women Combined group
2455 740 3195
13.38 (12.89–13.88) 3.87 (3.60–4.15) 8.52 (8.25–8.81)
222 84 306
1.21 (1.06–1.38) 0.44 (0.35–0.54) 0.82 (0.73–0.81)
300 61 361
1.64 (1.46–1.83) 0.32 (0.25–0.41) 0.96 (0.87–1.07)
42 2 44
0.23 (0.17–0.31) 0.01 (0.003–0.04) 0.12 (0.09–0.16)
Taiwanese Han Men Women Combined group
757 125 882
64 13 77
0.38 (0.30–0.49) 0.06 (0.03–0.01) 0.21 (0.16–0.26)
116 36 152
0.70 (0.58–0.84) 0.17 (0.12–0.24) 0.41 (0.34–0.48)
4 0 4
0.01 (0.004–0.03) – 0.01 (0.004–0.03)
4.55 (4.24–4.87) 0.60 (0.50–0.72) 2.36 (2.21–2.51)
ICD-9-CM: International Classification of Diseases, Ninth Revision, Clinical Modification; CI: confidence interval. Gouty arthropathy: ICD-9-CM 274.0 (gouty arthropathy) and 274.9 (gout, unspecified). Gouty nephropathy: ICD-9-CM 274.1 (gouty nephropathy), 274.10 (gouty nephropathy, unspecified), 274.11 (uric acid nephrolithiasis) and 274.19 (other gouty nephropathy). Gouty tophi: ICD-9-CM 274.8 (gout with other manifestations), 274.81 (gouty tophi of ear), 274.82 (gouty tophi of other sites, except ear) and 274.89 (gout with other specified manifestations). The prevalence of uric acid nephrolithiasis (274.11) was 0.42% (95% CI = 0.36–0.50) in aborigines (n = 159) and 0.09% (95% CI = 0.07–0.13) in Han (n = 35) in 2006. The prevalence of tophi (274.81 and 274.82) was 0.30% (95% CI = 0.25–0.36) in aborigines (n = 3 and n = 109) and 0.04% (95% CI = 0.03–0.07) in Han (n = 0 and n = 16) in 2006.
genders of both ethnic groups. Diabetes mellitus became insignificant after adjustment for age category, gender, and other comorbid disorders, except for marginal significance in female aborigines (OR 1.23, 95% CI 1.03–1.48; Supplementary data, Table S3). Heart failure was more frequently associated with gout in aborigines (men OR = 1.83, women OR = 1.54 and combined OR = 1.72) than in Han (only combined OR = 1.46). There was no significant difference for myocardial infarction. We also showed that gout was associated with men more than women in both aboriginal men (versus women, adjusted OR = 6.79) and Han men (versus women adjusted OR = 6.73), suggesting a gender contribution (Supplementary data, Table S3). Next, to separate the influences of non-comorbidity and comorbidity profiles, Tables 2 and 3 show the age distribution of gout prevalences and prevalence ratios between aborigines and Han, stratified by comorbidity status. In gout patients without comorbidity, the prevalence was higher for aborigines (men 7.76%, women 1.08%, combined 4.49%) than for Han (men 3.21%, women 0.24%, combined 1.52%). Similarly, in gout patients with comorbidity, the prevalence was higher for aborigines (men 45.98%, women 13.33%, combined 27.34%) than for Han (men 14.85%, women 3.90%, combined 9.44%). When stratified by comorbidity status, the prevalence ratio was approximately 3.00 for aborigines compared with Han. Additionally, the prevalence ratios of gout between the non-comorbidity group and the comorbidity group for aborigines and for Han were similarly increased for gout occurrence (PR = 6.09 and 6.23), implicating comorbidity as a determinant of gout risk, specifically, in early ages (20–29 years, PR = 8.58 and 12.47; Tables 2 and 3). We next performed separate analyses for aborigines and for Han to further investigate the impact of comorbidity on gout risk in both ethnicities (Tables 4 and 5). When the analysis was stratified by comorbid condition, the comorbid disorders of pure hypercholesterolemia (6.24%, 12.58%), pure hyperglyceridemia (6.21%, 12.73%), essential hypertension (89.17%, 75.92%), and renal insufficiency (11.81%, 20.40%) were important common comorbidities of gout in aborigines and Han (adjusted OR ≥ 1.63). We found that heart failure exerts a significant effect only in aborigines (adjusted OR = 1.55) and not in Han. Because patients with gout often have multiple comorbidities, we tested whether the effects of these additional comorbidities were associated with increased gout risk. We summarized this scenario by constructing a risk score combining pure hypercholesterolemia, pure hyperglyceridemia, essential hypertension, heart failure and renal insufficiency (range 0–5; Table 6). We found that the adjusted OR for gout risk increased steadily among gout patients by score category, from 1.85 to 9.16 in
aborigines and from 1.84 to 12.90 in Han, with a per comorbidity factor increased approximately 2-fold for gout prevalence. These findings show that the presence of multiple comorbidities is an important component for gout prevalence in Taiwan.
5. Discussion In 2006, gout prevalence was 10.42% in Taiwan aborigines and 2.98% in Taiwanese Han. We showed that uric acid nephrolithiasis and tophi had prevalences of 0.42% and 0.30%, respectively, of aborigines and 0.09% and 0.04%, respectively, of Han. We noted a substantial difference in gout prevalence between ethnicities (PR = 3.50). The prevalences of gout in the non-comorbidity and comorbidity groups were 4.49% and 27.34%, respectively, in aborigines and 1.52% and 9.44%, respectively, in Han (approximate PR = 3.00). We showed that comorbidity was the most significant determinant of gout risk (overall PR = 6.09 in aborigines and 6.23 in Han), specifically at early ages (20–29 years, PR = 12.47 in aborigines and 8.58 in Han). Pure hypercholesterolemia, pure hyperglyceridemia, essential hypertension, and renal insufficiency were important comorbidities for gout in both ethnicities. The magnitude of the four comorbidity associations did not differ between men and women (Table 5). We also found that heart failure exerts a significant effect on gout risk in aborigines (adjusted OR = 1.48 in men and 1.53 in women) but not in Han. For those patients with gout and multiple comorbid diseases, gout risk increased approximately two-fold for each comorbidity factor, which helps to explain gout prevalence in Taiwan. We found that the prevalence was higher among aborigines (4.49%) than Han (1.52%) in non-comorbid gout patients. Genetic and environmental factors may contribute to gout etiology [12,28–30]. In our previously study, the aborigines had a higher alcohol use (48% versus 24% in Han) and alcohol use to be more a significant predictor of tophaceous gout risk in aborigines than Han; aborigines of gout cases with carriers of ABCG2 Q141K [T/T] had an earlier age of visit to the clinician (39 years versus 43 years in Han) [29]. A population-based study has shown a substantial heritable component for gout (35.1% in men and 17.0% in women) [12]. Recent genome-wide association studies (GWAS) have identified multiple novel genetic variants, mostly of genes involved in the renal urate-transport system, that are associated with uric acid levels and gout susceptibility [28,31]. Therefore, finding the genetic determinants, such as the renal urate-transport genes ABCG2, SLC2A9 and SLC22A12 [28], of urate homeostasis is
48
F.-Y. Tu et al. / Joint Bone Spine 82 (2015) 45–51
Table 2 Prevalence of gout according non-comorbidity and comorbidity groups in Taiwan aborigines. Non-comorbidity group
Comorbidity group
Prevalence ratio (95% CI)
Gout, n
At risk population, n
Prevalence % (95% CI)
Gout, n
At risk population, n
Prevalence % (95% CI)
Men 20–29 years 30–39 years 40–49 years 50–59 years 60–69 years ≥ 70 years Overall
120 281 344 217 81 57 1100
4956 3785 3279 1451 448 258 14177
2.42 (2.03–2.9) 7.42 (6.61–8.35) 10.49 (9.44–11.66) 14.96 (13.09–17.08) 18.08 (14.54–22.48) 22.09 (17.04–28.64) 7.76 (7.31–8.23)
28 155 481 549 362 344 1919
117 431 1078 1164 731 653 4174
23.93(16.52–34.66) 35.96 (30.72–42.10) 44.62 (40.80–48.79) 47.16 (43.38–51.28) 49.52 (44.67–54.90) 52.68 (47.40–58.55) 45.98 (43.96–48.08)
Women 20–29 years 30–39 years 40–49 years 50–59 years 60–69 years ≥ 70 years Overall
4 17 45 32 19 30 147
4970 3585 3010 1198 443 373 13579
0.08 (0.03–0.21) 0.47 (0.29–0.76) 1.50 (1.12–2.00) 2.67 (1.89–3.78) 4.29 (2.74–6.72) 8.04 (5.62–11.50) 1.08 (0.92–1.27)
10 21 103 179 172 255 740
127 349 1213 1466 1072 1325 5552
7.87 (4.24–14.64) 6.02 (3.92–9.23) 8.49 (7.00–10.30) 12.21 (10.55–14.14) 16.04 (13.82–18.63) 19.25 (17.02–21.76) 13.33 (12.40–14.32)
97.83 (30.68–311.94) 12.69 (6.69–24.05) 5.68 (4.00–8.06) 4.57 (3.14–6.66) 3.74 (2.33–6.01) 2.39 (1.64–3.49) 12.31 (10.32–14.70)
124 298 389 249 100 87 1247
9926 7370 6289 2649 891 631 27756
1.25 (1.05–1.49) 4.04 (3.61–4.53) 6.19 (5.60–6.83) 9.40 (8.30–10.64) 11.22 (9.23–13.65) 13.79 (11.17–17.01) 4.49 (4.25–4.75)
38 176 584 728 534 599 2659
244 780 2291 2630 1803 1978 9726
15.57 (11.33–21.40) 22.56 (19.46–26.16) 25.49 (23.51–27.64) 27.68 (25.74–29.77) 29.62 (27.21–32.24) 30.28 (27.95–32.81) 27.34 (26.32–28.40)
12.47 (8.67–17.93) 5.58 (4.63–6.72) 4.12 (3.63–4.69) 2.94 (2.55–3.40) 2.64 (2.13–3.27) 2.20 (1.75–2.75) 6.09 (5.69–6.51)
Combined group 20–29 years 30–39 years 40–49 years 50–59 years 60–69 years ≥ 70 years Overall
9.88 (6.55–14.91) 4.84 (3.98–5.89) 4.25 (3.70–4.88) 3.15 (2.70–3.69) 2.74 (2.15–3.49) 2.38 (1.80–3.16) 5.93 (5.50–6.38)
Prevalence ratio with 95% confidence interval (CI) was estimated by the log-binomial model.
important because elevated serum uric acid levels, the formation of urate microcrystals and the attraction and activation of susceptible phagocytes are important. Patients with gout often have multiple comorbidities, and there is an increasing body of evidence showing that hyperuricemia is associated with hypertension, heart failure, and chronic kidney disease [25]. Moreover, about 64.5% of hyperuricemic children and adolescents are obesity [32]; a relatively high proportion of Taiwanese hyperuricemic children and adolescents are affected by hypercholesterolemia and hyperglyceridemia, 67.9% and 61.8%,
respectively [23], and 50–70% of hyperglyceridemic patients have gout, indicating that hyperglyceridemia is an important serum urate determinant [33]. Between the two coexisting illnesses, we observed that hyperglyceridemia was a stronger independent comorbid factor for gout risk than hypercholesterolemia in both ethnic groups (OR ≥ 2.57 versus OR ≥ 1.89). Hypertriglyceridemia is an independent risk factor in men on gout development with and without hyperuricemia (hazard ratios 1.38 and 1.40) [34]. Furthermore, hypertension was an independent risk factor for gout after adjusting for diuretics [24], and 17.5–59.7% of hypertensive
Table 3 Prevalence of gout in non-comorbidity and comorbidity groups in Taiwanese Han. Non-comorbidity group
Comorbidity group
Prevalence ratio (95% CI)
Gout, n
At risk population, n
Prevalence % (95% CI)
Gout, n
At risk population, n
Prevalence % (95% CI)
Men 20–29 years 30–39 years 40–49 years 50–59 years 60–69 years ≥ 70 years Overall
43 168 112 67 23 9 422
2987 5438 2786 1243 484 217 13,155
1.44 (1.07–1.94) 3.09 (2.66–3.59) 4.02 (3.34–4.84) 5.39 (4.24–6.85) 4.75 (3.16–7.15) 4.15 (2.16–7.97) 3.21 (2.92–3.53)
14 65 148 139 87 66 519
105 549 853 882 627 479 3495
13.33 (7.90–22.52) 11.84 (9.28–15.10) 17.35 (14.77–20.38) 15.76 (13.35–18.61) 13.88 (11.25–17.12) 13.78 (10.82–17.54) 14.85 (13.63–16.18)
Women 20–29 years 30–39 years 40–49 years 50–59 years 60–69 years ≥ 70 years Overall
6 10 9 7 5 4 41
5782 6632 2923 1404 390 258 17,389
0.10 (0.05–0.23) 0.15 (0.08–0.28) 0.31 (0.16–0.59) 0.50 (0.24–1.05) 1.28 (0.53–3.08) 1.55 (0.58–4.13) 0.24 (0.17–0.32)
1 3 20 40 27 42 133
208 426 581 898 572 727 3412
0.48 (0.07–3.42) 0.70 (0.23–2.18) 3.44 (2.22–5.34) 4.45 (3.27–6.07) 4.72 (3.24–6.88) 5.78 (4.27–7.82) 3.90 (3.29–4.62)
4.63 (0.56–38.48) 4.67 (1.29–16.97) 11.18 (5.09–24.55) 8.93 (4.00–19.94) 3.68 (1.42–9.56) 3.73 (1.34–10.39) 16.53 (11.65–23.46)
Combined group 49 20–29 years 178 30–39 years 40–49 years 121 74 50–59 years 28 60–69 years 13 ≥ 70 years 463 Overall
8769 12,070 5709 2647 874 475 30,544
0.56 (0.42–0.74) 1.48 (1.27–1.71) 2.12 (1.77–2.53) 2.80 (2.23–3.51) 3.20 (2.21–4.64) 2.74 (1.59–4.71) 1.52 (1.38–1.66)
15 68 168 179 114 108 652
313 975 1434 1780 1199 1206 6907
4.79 (2.89–7.95) 6.97 (5.50–8.85) 11.72 (10.07–13.63) 10.06 (8.69–11.64) 9.51 (7.91–11.42) 8.96 (7.42–10.81) 9.44 (8.74–10.19)
8.58 (4.81–15.29) 4.73 (3.58–6.25) 5.53 (4.38–6.98) 3.60 (2.74–4.72) 2.97 (1.96–4.49) 3.27 (1.84–5.82) 6.23 (5.53–7.02)
Prevalence ratio with 95% confidence interval (CI) was estimated by the log-binomial model.
9.26 (5.07–16.93) 3.83 (2.88–5.10) 4.32 (3.38–5.52) 2.92 (2.18–3.91) 2.92 (1.84–4.62) 3.32 (1.66–6.67) 4.63 (4.07–5.26)
Table 4 Association between comorbidity and gout in comorbidity group. Men
Crude OR (95% CI)
Women
Crude OR (95% CI)
Combined group
Crude OR (95% CI)
Controls
Gout cases
Controls
Gout cases
Controls
1919 55.79 (12.99)
2255 52.83 (13.87)
1.02 (1.01–1.02)
740 62.27 (13.33)
4812 57.10 (14.24)
1.03 (1.02–1.03)
431 (22.46) 106 (5.52) 122 (6.36) 27 (1.41) 1693 (88.22) 57 (2.97) 158 (8.23) 232 (12.09)
662 (29.36) 74 (3.28) 82 (3.64) 28 (1.24) 1824 (80.89) 54 (2.39) 117 (5.19) 168 (7.45)
0.70 (0.61–0.80) 1.72 (1.27–2.33) 1.80 (1.35–2.40) 1.14 (0.67–1.93) 1.77 (1.49–2.11) 1.25(0.86–1.82) 1.64 (1.28–2.10) 1.71 (1.39–2.11)
218 (29.46) 60 (8.11) 43 (5.81) 14 (1.89) 678 (91.62) 26 (3.51) 112 (15.14) 82 (11.08)
1219 (25.33) 250 (5.20) 118 (2.45) 111 (2.31) 4088 (84.95) 119 (2.47) 439 (9.12) 322 (6.69)
1.23 (1.04–1.46) 1.61 (1.20–2.16) 2.45 (1.72–3.51) 0.82 (0.47–1.43) 1.94 (1.48–2.54) 1.44 (0.93–2.21) 1.78 (1.42–2.22) 1.74 (1.35–2.24)
2659 57.59 (13.40) 1919 (72.17) 649 (24.41) 166 (6.24) 165 (6.21) 41 (1.54) 2371 (89.17) 83 (3.12) 270 (10.15) 314 (11.81)
7067 55.74 (14.26) 2255 (31.91) 1881 (26.62) 324 (4.58) 200 (2.83) 139 (1.97) 5912 (83.66) 173 (2.45) 556 (7.87) 490 (6.93)
1.01 (1.01–1.01) 5.53 (5.02–6.11) 0.89 (0.80–0.99) 1.39 (1.14–1.68) 2.27 (1.84–2.81) 0.78 (0.55–1.11) 1.61 (1.40–1.85) 1.28 (0.99–1.68) 1.32 (1.14–1.54) 1.80 (1.55–2.09)
Taiwanese Han, n Age (SD), years Men, n (%) Diabetes mellitus, n (%) Pure hypercholesterolemia, n (%) Pure hyperglyceridemia, n (%) Obesity, n (%) Essential hypertension, n (%) Myocardial infarction, n (%) Heart failure, n (%) Renal insufficiency, n (%)
519 52.80 (13.05)
2976 52.97 (13.91)
1.00(0.99–1.01)
133 61.56 (13.14)
3279 54.89 (15.92)
1.03 (1.02–1.04)
141 (27.17) 60 (11.56) 62 (11.95) 10 (1.93) 385 (74.18) 24 (4.62) 33 (6.36) 104 (20.04)
1051 (35.32) 227 (7.63) 178 (5.98) 38 (1.28) 2037 (68.45) 125 (4.20) 150 (5.04) 353 (11.86)
0.68 (0.56–0.84) 1.58 (1.17–2.14) 2.13(1.57–2.90) 1.52 (0.75–3.07) 1.32 (1.07–1.64) 1.11 (0.71–1.73) 1.28 (0.87–1.89) 1.86 (1.46–2.37)
50 (37.59) 22 (16.54) 21 (15.79) 4 (3.01) 110 (82.71) 5 (3.76) 15 (11.28) 29 (21.80)
1101 (33.58) 306 (9.33) 142 (4.33) 153 (4.67) 2200 (67.09) 91 (2.78) 214 (6.53) 469 (14.30)
1.19 (0.83–1.71) 1.93 (1.20–3.09) 4.14 (2.52–6.80) 0.63 (0.23–1.74) 2.35 (1.49–3.70) 1.37 (0.55–3.43) 1.82 (1.05–3.17) 1.67 (1.09–2.55)
652 54.59 (13.53) 519 (79.60) 191 (29.29) 82 (12.58) 83 (12.73) 14 (2.15) 495 (75.92) 29 (4.45) 48 (7.36) 133 (20.40)
6255 53.98 (15.03) 2976 (47.58) 2152 (34.40) 533 (8.52) 320 (5.12) 191 (3.05) 4237 (67.74) 216 (3.45) 364 (5.82) 822 (13.14)
1.00 (0.99–1.01) 4.30 (3.53–5.24) 0.79 (0.66–0.94) 1.54 (1.21–1.98) 2.71 (2.10–3.50) 0.70 (0.40–1.21) 1.50 (1.25–1.81) 1.30 (0.88–1.94) 1.29 (0.94–1.76) 1.69 (1.38–2.08)
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Gout cases Taiwan aborigines, n Age (SD), years Men, n (%) Diabetes mellitus, n (%) Pure hypercholesterolemia, n (%) Pure hyperglyceridemia, n (%) Obesity, n (%) Essential hypertension, n (%) Myocardial infarction, n (%) Heart failure, n (%) Renal insufficiency, n (%)
Crude odds ratio (OR) with 95% confidence interval (CI) in parentheses was estimated according to gender and ethnicity using a logistic regression model.
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Table 5 Multivariate odds ratios of comorbid factors for gout risk in comorbidity group. Taiwan aborigines
Age, years Men Diabetes mellitus Pure hypercholesterolemia Pure hyperglyceridemia Obesity Essential hypertension Myocardial infarction Heart failure Renal insufficiency
Taiwanese Han
Men
Women
Combined group
Men
Women
Combined group
Adjusted OR (95% CI)
Adjusted OR (95% CI)
Adjusted OR (95% CI)
Adjusted OR (95% CI)
Adjusted OR (95% CI)
Adjusted OR (95% CI)
1.01 (1.01–1.02)
1.02 (1.02–1.03)
–
1.02 (1.01–1.03)
0.76 (0.65–0.88) 1.80 (1.31–2.47) 2.24 (1.66–3.04) – 1.81 (1.48–2.20) – 1.48 (1.14–1.92) 1.94 (1.55–2.41)
– 1.55 (1.14–2.11) 3.28 (2.25–4.79) – 2.02 (1.51–2.69) – 1.53 (1.21–1.94) 2.06 (1.57–2.71)
1.02 (1.01–1.02) 6.27 (5.65–6.95) – 1.63 (1.31–2.03) 2.57 (2.02–3.28) – 2.00 (1.71–2.34) – 1.55 (1.30–1.84) 2.00 (1.68–2.37)
0.76 (0.61–0.94) 1.82 (1.34–2.48) 2.59 (1.89–3.55) – 1.60 (1.27–2.01) – – 2.21 (1.72–2.86)
– 1.85 (1.12–3.05) 4.62 (2.74–7.80) – 2.55 (1.56–4.19) – – 2.36 (1.51–3.69)
– 4.38 (3.59–5.35) – 1.89 (1.46–2.46) 3.02 (2.30–3.96) – 1.96 (1.61–2.40) – – 2.33 (1.87–2.90)
Adjusted odds ratios (OR) with 95% confidence intervals (CI) in parentheses were estimated according to gender and ethnicity using a stepwise multiple logistic regression model; only significant variables were entered to this model (P < 0.05) otherwise indicated by ‘–’.
Caucasians are estimated to have gout [10,35]. We found that the independent effect of hypertension for both ethnic groups (OR = 4.53 and OR = 4.24) was most evident in the general population of aborigines compared with Han (60.70% and 44.39%). Similarly, the consistency of results for this comorbid condition supports the presence, among general populations, of an association between hypertension and gout (89.17% and 75.92%; OR ≥ 1.96). Additionally, we found that heart failure exerts a significant effect on gout risk only in aborigines. A related issue is that heart disease occurrence is rising in developed countries and is linked to serum uric acid levels [18]. In this study, heart failure was independently linked to gout risk in the general populations (aborigines OR = 1.72; Han OR = 1.46), but this association was more significant in aborigines than in Han (P for interaction = 0.0067). The association between heart failure and gout was consistent among subjects in the comorbid condition group. Interestingly, we found similar proportions of gouty nephropathy and uric acid nephrolithiasis (ICD-9-CM: 274.10–274.19) in aborigines 8.96% (350/3906) and in Han 7.26% (81/1115; Table 1). This suggests that the sequelae of chronic gout may include crystal deposition in the kidneys that could predispose patients to arteriosclerosis and interstitial fibrosis [1–3]. Renal impairment is a significant risk factor for gout [5]. Advanced arteriolosclerosis, glomerulosclerosis and interstitial fibrosis are associated with urate crystal aggregates in the outer medulla [18]. The independent effect of renal insufficiency on gout risk was significant in both ethnic groups, both in the general populations and in the subjects with comorbid conditions (OR = 2.69 and OR = 3.11; OR = 2.00 and OR = 2.23). However, because the daily turnover of uric acid includes two-thirds clearance through urinary excretion and one-third clearance by the gut [1], renal insufficiency is likely to disrupt this physiological process. Together, these findings for the five coexistent illnesses suggest additional reasons for
the lower background incidence of gout that go beyond the lower baseline serum uric acid levels. Obesity and insulin resistance correlate with gout [36]. A retrospective analysis in the UK found that obesity is most associated with gout [10]. Although less than 3% of aborigines and Han with gout were obese compared to 27.7% in the UK study, obesity was still independently associated with risk of gout in patients from both ethnic groups (OR ≥ 2.19). In the present study, there was a similar concordance with diabetes, 16.62% in aborigines and 17.13% in Han, but lower than the co-occurrences of gout and diabetes reported for Germany, 25.9%, and the US, 19.9% [10,35]. The subjects with comorbidities had a higher frequency of diabetes among goutfree controls (26.62 and 34.40% in aborigines and Han) than among gout patients (24.41% and 29.29), which could explain the low association with gout in this data set. However, the co-occurrences of gout and diabetes still had a higher frequency in both ethnicities. Furthermore, from the NHANES data, mortality due to myocardial infarction is 1.77-fold in men and 3.00-fold in women after comparing the highest and lowest quartiles for serum urate [19]. In MRFIT, a relationship between gout and the risk of acute myocardial infarction was evident among those with and without hyperuricemia [37]. In a cohort study from the Taiwan National Health Insurance Database, a risk of myocardial infarction was demonstrated among those with and without gout [38]. However, we failed to observe a relationship between gout and myocardial infarction in this cross-sectional data set. There are several limitations to be noted regarding this study. The BNHI is primarily a health insurance database that contains limited information on criteria for clinical diagnosis (e.g., urate crystals in joint fluid in gout patients, uric acid levels) and on environmental factors (e.g., lifestyle habits, alcohol use) [12]. Poor validation of medical record ICD-9 diagnoses of gout in a veterans
Table 6 Comorbidity aggregations in gout patients in comorbidity group. Taiwan aborigines
Gout cases Risk score 120 (4.51) 0 1 1921 (72.25) 505 (18.99) 2 97 (3.65) 3 16 (0.60) 4
Adjusted OR (95% CI)
Controls 620 (8.77) 5512 (78.00) 846 (11.97) 78 (1.10) 11 (0.16)
1.00 1.85 (1.49–2.29) 3.47 (2.72–4.42) 6.92 (4.68–10.21) 9.16 (3.87–21.70)
Taiwanese Han
Gout cases
Controls
52 (7.98) 406 (62.27) 151 (23.16) 39 (5.98) 4 (0.61)
1008 (16.12) 4357 (69.66) 759 (12.13) 123 (1.97) 8 (0.13)
Adjusted OR (95% CI)
1.00 1.84 (1.36–2.49) 3.97 (2.83–5.58) 7.56 (4.68–12.20) 12.90 (3.48–47.85)
Combined group
Gout cases
Controls
172 (5.19) 2327 (70.28) 656 (19.81) 136 (4.11) 20 (0.60)
1628 (12.22) 9869 (74.08) 1605 (12.05) 201 (1.51) 19 (0.14)
Adjusted OR (95% CI)
1.00 1.85 (1.55–2.20) 3.58 (2.94–4.36) 7.03 (5.20–9.51) 10.08 (4.85–20.93)
A risk score was generated for every individual by counting the disease status associated with gout (pure hypercholesterolemia, pure hyperglyceridemia, essential hypertension, heart failure and renal insufficiency; range 0–5). The comorbidity aggregations of score = 5 was no found in this data set. Adjusted ORs were adjusted for age and sex, and for combined group, the ethnicity using a multiple logistic regression model.
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affairs database is seen [39]. However, the utility and validity of gout diagnoses in claims databases have been assessed and have been shown to be reasonably robust [40]. In addition, our estimate of gout prevalence is similar to that reported in some studies in Taiwan (11.7% in aborigines; 3.0% in Han) [16,17]. In conclusion, we have observed a substantial risk of gout with comorbid diseases, specifically in early age, in Taiwan aborigines and Taiwanese Han. In gout patients without comorbidity, the prevalence of gout was higher among aborigines than Han, suggesting that genetic and environmental factors contribute to gout etiology. Therefore, primary prevention of gout should prompt evaluation for potentially modifiable risk factors (e.g., gout susceptibility genes and dietary habits) and important associated coexisting illness (e.g., pure hypercholesterolemia, pure hyperglyceridemia, essential hypertension, renal insufficiency and heart failure) that may require intervention. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgements We thank the Bureau National Health Insurance for supplying the data. Funding: This works was supported by Kaohsiung Medical University [KMU-M103018] and [KMUH99-9R17]. Appendix A. Supplementary data Supplementary data (Tables S1–S3) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.jbspin.2014.07.002. References [1] Richette P, Bardin T. Gout. Lancet 2010;375:318–28. [2] Terkeltaub RA. Clinical practice. Gout. N Engl J Med 2003;349:1647–55. [3] Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann Intern Med 2005;143:499–516. [4] 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. [5] Roddy E, Zhang W, Doherty M. The changing epidemiology of gout. Nat Clin Pract Rheumatol 2007;3:443–9. [6] Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum 2008;58:26–35. [7] Adams JU. New relief for gout. Nat Biotechnol 2009;27:309–11. [8] Yu KH, See LC, Kuo CF, et al. Prevalence and incidence in patients with autoimmune rheumatic diseases: a nationwide population-based study in Taiwan. Arthritis Care Res (Hoboken) 2013;65:244–50. [9] Harris CM, Lloyd DC, Lewis J. The prevalence and prophylaxis of gout in England. J Clin Epidemiol 1995;48:1153–8. [10] Annemans L, Spaepen E, Gaskin M, et al. Gout in the UK and Germany: prevalence, comorbidities and management in general practice 2000–2005. Ann Rheum Dis 2008;67:960–6. [11] Kuo CF, Grainge MJ, Mallen C, et al. Rising burden of gout in the UK but continuing suboptimal management: a nationwide population study. Ann Rheum Dis 2014, doi:10.1136/annrheumdis-2013-204463.
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