Although the prevalence of hyperuricemia varied according to different regions and ethnicities, most studies are consistent with the incremental trend of hyperuricemia (Figure 1) [6-9]. In Korea, there have been several studies on hyperuricemia (Table 1 and Figure 1). A cohort study has reported that a seven-year cumulative incidence of hyperuricemia was 23.1% in Korean male workers of 30~59 years of age in one of the largest semiconductor manufacturing companies in Korea [10]. The prevalence of hyperuricemia in 2002 was 9.3% among those who participated in the health check-up program [11]. A single-center study in a sample of 2,297 participants reported that the prevalence of hyperuricemia between 2008 and 2010 was 9.8% [12]. These two studies reported similar prevalence of hyperuricemia, which had a common point in that they used the same definition of hyperuricemia as the examinees of health checkup center of the tertiary hospital. Two epidemiological studies using the national surveillance data also gave report regarding the prevalence of hyperuricemia in Korean population. The age-standardized prevalence of hyperuricemia has been estimated at 11.4% in the 2016 Korean National Health and Nutrition Examination survey (KNHANES) data [13]. The overall prevalence of hyperuricemia was 5.1% based on the data collected between 2004 and 2013 from the Korean Genome and Epidemiology Study [14]. As shown in Table 1, the prevalence of hyperuricemia varies, ranging from 5.1% to 11.4% in Korea. The discrepancies among these studies might be due to the differences in the definition of hyperuricemia, duration of data collection, estimate methodology, and timeframe of the study. Overall, the prevalence of hyperuricemia in Korea tends to increase over the years as in other countries worldwide, but a relatively faster increase in women than that in men was observed in Korea. The increasing prevalence of hyperuricemia has been perceived as an emerging public health concern worldwide.

Reported estimates of gout prevalence range from 2.7% to 6.7% in countries (Figure 2) [6,15-19]. The most recent estimate of the lifetime prevalence of a health professional-diagnosed gout in the USA was 3.9% (5.2% in men and 2.7% in women) in 2015~2016 [16]. On analyzing 2007~2016 National Health and Nutrition Examination Survey (NHANES) data by race, the prevalence of gout was 4.8%, 4%, and 2% in African Americans, Caucasians, and Hispanics, respectively [16]. Greece has the highest prevalence of gout in Europe, approaching 4.75% of the adult population [17]. In a nationwide register-based retrospective study during the 20-year study period (1995~2015) in Denmark, the estimated prevalence of gout was 0.6% in 2000, with a significant increase, up to 0.87% in 2015, an increase by approximately 45% over 15 years [19].

As shown in Figure 2, gout is particularly prevalent in Taiwan aborigines and Polynesian peoples [20,21]. Thus, genetic variation may partly explain the higher prevalence of gout in this region. In a meta-analysis of studies reported between 2000 and 2016, the pooled estimate of gout prevalence was 1.6% in China, varying from 0.8% to 5% by regions [22]. The overall prevalence for physician-diagnosed gout was 1.14% in Eastern China [23]. In the study using Japan Medical Data Center database, the prevalence of gout was 0.82% in 2010, with a slight increase, up to 0.88% in 2014 (1.66% in men and 0.09% in women) [24]. In a cross-sectional study using Japanese claims database, the prevalence of gout was 1.1% (1.9% in men and less than 0.1% in women) [8].

In Korea, three epidemiological studies using the Health Insurance Review & Assessment (HIRA) data reported the prevalence of gout (Table 2 and Figure 2). In the HIRA database over the period 2001–2008, the prevalence of gout was 0.17% in 2001 and 0.40% in 2008, with a 2.3-fold increase over seven years [25]. In the Korean claims database for the period 2007~2015, the prevalence of gout was significantly higher in 2015 than that in 2007, with an approximately 2.3-fold increase from 0.35% in 2007 to 0.76% in 2015 [26]. In the claims database for the period 2002~2015, the prevalence of gout increased approximately five-fold, from 0.39% in 2002 to 2.01% in 2015 [27]. Although significant differences in its prevalence were found among three nationwide population studies, the rate of increase in prevalence between 2007 and 2015 was almost similar, suggesting that gout prevalence continued to increase in Korea rapidly and significantly over the past eight years.

Globally, including Korea, it is common that gout is frequent in advanced age or middle-aged men. The prevalence of gout in Korea seems to be lower than that in Western developed countries and Taiwan. As shown in Figure 2, recent estimates indicate that the prevalence of gout seems to have reached a plateau in North America while it seems to continue to increase rapidly in Europe and Asia.

Serum uric acid (SUA) has been known to be a double-edged sword with pro-inflammatory as well as antioxidant effects in the body. Gout is a common hyperuricemic metabolic condition that is complicated by an increased burden of various comorbidities.

According to the third NHANES, gout is associated with increased prevalence of coexistent hypertension, obesity, diabetes mellitus, CKD, myocardial infarction (MI), heart failure, and stroke [28]. Similarly, using the National Health Insurance Service (NHIS) database, it was reported that Korean population with gout had increased risks for acute MI, ischemic heart disease, and cardiovascular (CV) disease, in descending order [29]. In each study conducted at the same tertiary hospital in 2004 and 2016, respectively, the frequency of metabolic syndrome in gout patients showed a trend towards an increase in 2016 compared to that in 2004 (50.8 vs. 42.2%) [30,31]. The Korean population with gout was associated with an increased prevalence of hypertension (79%), obesity (49%), and diabetes mellitus/hyperglycemia (33%) [31]. Further, in an analysis using the NHIS database, the prevalence of metabolic syndrome in the Korean population with gout was significantly higher than that in the control group (44% vs. 5.2%) [32].

There are multiple studies on the relationship between SUA levels and mortality. In all inhabitants of Japan who were between 40 and 74 years of age, all-cause and CV mortality rates in participants with hyperuricemia were significantly increased compared with those with normouricemia (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.25~1.49 for all-cause mortality and HR, 1.69; 95% CI, 1.41~2.01 for CV mortality) [7]. The burden of death attributable to hyperuricemia in Korea is not well quantified. In a large-scale cohort study in Korea, adults in the highest SUA categories (≥9.5 mg/dL for men and ≥8.5 mg/dL for women) were 2.39 (95% CI, 1.57~3.66) in men and 3.77 (95% CI, 1.17~12.17) in women for all-cause mortality, respectively, suggesting that a substantial number of all-cause deaths were attributed to hyperuricemia [33]. Management of various comorbidities in the Korean population with gout or hyperuricemia needs to be considered.

Previous studies have reported that uric acid may be one of the most important antioxidants in the blood. There are studies on the association between gout or SUA level and several neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis (Table 3) [34-41]. There was no consistent relationship between SUA level and dementia or cognitive impairment based on a meta-analysis [36]. Risk of dementia, especially vascular or mixed dementia, may be increased with high SUA levels in elderly people [37]. Few studies have explored the association between gout or hyperuricemia and neurodegenerative diseases in Korea [39,40]. In a retrospective cohort study using Korea NHIS data, gout has been shown to be inversely related to the risk for overall dementia, especially in elderly men. On the other hand, after adjusting for age and sex, the risk for vascular dementia in gout patients increased by approximately 2.3 times in non-elderly men. In this study, the association between gout and dementia showed different results according to age or type of dementia [40]. Studies on the association between gout or hyperuricemia and Parkinson's disease have also yielded conflicting results. In a meta-analysis, hyperuricemia significantly reduced the risk for Parkinson’s disease, and the SUA level tended to decrease as the disease progresses [35]. Based on the US Medicare data between 2006 and 2012, hyperuricemia increased the risk for incidental Parkinson’s disease by 27% in elderly people [38]. Furthermore, a population-based retrospective cohort study in Taiwan did not reveal any significant results between gout and Parkinson’s disease [41]. Similar to that of a previous Taiwan study, the Korean patients with gout were not associated with an increased risk for Parkinson’s disease in a nationwide population-based cohort [39]. One of the limitations of this study may be the lack of adjustment for various confounding factors that may affect dementia considering the inherent nature of NHIS database. Considered together, although the association between hyperuricemia or gout and neurodegenerative diseases has been investigated in various published studies, their causal relationship is still unclear.

The pro-oxidant and anti-oxidant properties of uric acid have been postulated to play an important role in tumorigenesis [42]. For example, a study of US veterans reported that the 10-year prevalence of colorectal cancer was significantly lower among gout patients than that in osteoarthritis patients despite the adjustment for the use of colchicine, allopurinol, and/or non-steroidal anti-inflammatory drugs [43]. Based on the National Health Insurance Database in Taiwan, the risk for overcall cancer was 1.15-time elevated among patients with gout [44]. Furthermore, analysis of Swedish nationwide hospital discharge system identified 1.25-time higher risk to develop cancer in gout patients [45]. In a meta-analysis, hyperuricemia or gout was associated with higher cancer incidence and mortality [46]. Recently, two nationwide population-based studies reported regarding the cancer risk in Korean patients with gout [47,48]. Overall, the cancer risk was 1.2-time higher in middle-aged patients with gout compared to that in controls, while the all-cause mortality and cancer mortality were 1.5-time higher. In the sub-analysis of cancer subtype, the risk was increased in the order of gastric cancer, head and neck cancer, and hematologic malignancy. The risk for colon cancer was 30% lower in gout patients but was of borderline significance [48]. The other study using database from 2011~2015 reported overall cancer risk was weakly significant among those ≥20 years of age with gout (HR, 1.05; 95% CI, 1.03~1.08) [47]. The risk for stomach cancer was similarly increased in both studies, but the risk for other cancer types, including head and neck cancer, colon cancer, and hematologic malignancy, showed conflicting results between the two studies. One of the reasons for this difference is that the study of Lee et al. [48] was restricted to the patients of 41–55 years of age with gout. Considered together, although the risk for specific cancer type including colorectal cancer is conflicting in gout patients, it is considered a common opinion that the overall risk for cancer is increased in gout patients. It is difficult to give a definite cause for the increased risk of cancer in patients with gout. As one of the various reasons, the pro-inflammatory properties of uric acid have been postulated to play an important role in the pathogenesis of cancer. Also, gout sits at the intersection of inflammatory disease and metabolic disease such as diabetes, hypertension, hyperlipidemia, and obesity. These metabolic diseases are also associated with excess cancer, and chronic inflammation [42]. These may be an important link between gout and the development of cancer.

Many studies have been reported on the impact of SUA on various diseases [33-40,44-58]. For example, higher SUA levels were related to a reduced risk for lower urinary tract symptoms and was positively associated with lung function among clinically healthy middle-aged men [49,53]. On the contrary, hyperuricemia was associated with decreased lung function in the female general population [55]. In addition, a cross-sectional study demonstrated a positive association in men between SUA and lumbar spine bone mineral density (BMD), while Mendelian randomization analysis did not support a causal association between SUA level and lumbar spine or femur neck BMD [52,56]. Higher SUA level may have opposing effects depending on tissue type, sex, and age. Further studies are necessary to confirm and explain the relationship between specific disease conditions and hyperuricemia.

A systematic review on the economic burden of gout found that it ranged from $172 to $6,179, depending on population characteristics [59]. This showed positive associations of direct medical costs with SUA level, attack frequency, or presence of tophi [59]. The estimated economic burden for new cases of acute gout is reported to be $27 million yearly in the US [60]. In a cross-sectional study, patients with uncontrolled gout had higher total medical costs than those with well-controlled gout and without gout [61]. These results suggest that medical costs can be reduced by controlling the acute gout attacks. The economic burden of gout is most easily assessed in patients with acute gouty attack, resulting in emergency department visits, hospitalization, and work productivity loss [2]. However, the burden of illness of gout is not well documented in Korea. Recently, a study reported a large increase in hospital visits for gout between 2010 and 2017, especially emergency department visit, in Korea. Before 2013, the number of emergency room visits was high in the elderly over 70 years old, but after 2013, the number of visits to the relatively young middle-aged people of 30~50 years of age was the highest [62]. The most frequent visit to emergency room was among those in their 40s who were socially active and concerned of increase in healthcare resource utilization and indirect medical costs. In addition, care by rheumatologists for gouty attack is reported to reduce the economic burden [60]. The substantial economic burden may be attributed to increasing prevalence of gout and suboptimal treatment. These suggest that rheumatologists have an important role to play in reducing the economic cost of gout care despite methodologic limitations.

Currently, many countries have published gout treatment guidelines that suit their medical environment. Many guidelines recommend weight reduction as a non-pharmacologic measure for gout management despite the lack of sufficient data to support the possible decrease of SUA levels by weight reduction. Recent studies have confirmed that weight loss, achieved by dietary intervention or bariatric surgery, is effective in reducing SUA levels [63-65]. Among men with high CV risk observed over a seven-year period, the effect of weight reduction of ≥10 kg on achieving target level increased by approximately four-fold and its corresponding SUA level change was –0.62 mg/dL [64]. A retrospective observational study for the association between each body composite and SUA level was recently published based on clinically apparent healthy Korean participants [66,67]. The impact of fat mass change on SUA levels was modest, as every 1-kg fat mass reduction correlated to a 0.06-mg/dL decrease in SUA levels among clinically apparently healthy men [66]. Further, as body mass index (BMI) decreased by one unit, the probability of reaching the therapeutic target of SUA increased by 18% [67]. Although this study is a cross-sectional study and not an interventional study, it is the first study to analyze the relationship between change of body composite and alteration of SUA levels in the Korean population. Although the odds of these studies in achieving normouricemia were relatively small, this may provide the basis for healthcare providers to comment on the relationship between fat mass or BMI changes and SUA levels in men with asymptomatic hyperuricemia.

Gout still remains poorly managed in the general population. The prescription of urate-lowering therapy (ULT) is not adequately applied to the extent that only a third to half of patients with gout receive ULT [3]. Drug adherence in gout is reported to be among the poorest of several chronic diseases such as hypertension, diabetes, or rheumatoid arthritis [68]. One of the reasons for suboptimal treatment of gout is poor adherence to ULT. In a large retrospective claims analysis, 55% of patients with gout started allopurinol. Of these, more than 50% had a significant interruption in medication. The percentage of patients reaching target SUA levels (<6 mg/dL) was 49.3%~56.8% among the adherent participants and 22.5%~27.8% of non-adherent participants [69]. Adherence to ULT in patients with gout worldwide varied, ranging from 17% to 78% in prescription/claims studies [70]. Table 4 summarizes studies on the compliance of urate-lowering drugs in Korean patients with gout. Two prospective observational cohort studies were conducted in a tertiary hospital using pills monitored by the nurse, which showed higher adherence compared to those in previous studies [71,72]. The authors explained that the differences were due to study design (retrospective analyses vs. a prospective observational cohort study), willingness of volunteered patients, education about the rationale and goals of ULT, and prescription by rheumatologists rather than a primary care physician [71]. The adherence of ULT was reported to be 89.1% in a brief paper-based survey, which was conducted on patients with physician-diagnosed gout visiting the rheumatology outpatient clinics of 16 tertiary hospitals [73]. Factors related to good adherence included the elderly, better knowledge of gout management strategies, and the preference for ULT. Based on HIRA database 2007 to 2015, ULT was reported to be prescribed in more than 80% of Korean patients with gout [74]. Of these, only 35% of the patients were continuously prescribed ULT during five years. In summary, as shown in Table 4, adherence to ULT in Korea reported various results, ranging from 33% to 89.1%, according to study design or data collection time [71-74]. Even if gout is one of the curable rheumatic diseases using inexpensive and effective medications, appropriate treatment is not being performed worldwide, including Korea, suggesting that new measures are needed, along with continuous efforts to overcome poor compliance to ULT.

Urate-lowering drugs were grouped based on their mechanism of action. Urate-lowering drugs available in Korea are as follows: allopurinol, febuxostat, and benzbromarone. Despite effective ULT, potential serious adverse effects including allopurinol hypersensitivity syndrome (AHS) have become an obstacle to ULT use in the past. Recently, the use of febuxostat has raised concern in gout patients with high CV risk. There has been a debate whether febuxostat may increase the risk of CV events in gout patients [75,76]. In this regard, CARES trial results were reported in 2019. This caused febuxostat to be a second-line drug in patients with major CV disease, but subsequent studies after the CARES trial results have not replicated the result of the CARES trial [77-79]. Furthermore, for various reasons, it may be unreasonable to apply these evidences directly to Korean population with gout. In addition to several limitations of the CARES trial, only a small portion of Asians were included in this study. Further, using 2002~2015 Korean NHIS data, no significant difference in the risk for CV events and all-cause mortality between febuxostat and allopurinol users was reported after minimizing confounding [80], suggesting that there is no direct evidence that febuxostat increases the risk for CV disease in Korean patients with gout. Based on these findings, febuxostat has been still used as the first-line drug in Korean patients with gout. Some studies explain that the increase in CV events in gout is not due to the drug, but rather due to the rapid change in SUA level that occurs after ULT discontinuation or “sick-stopper” effect [81-83]. The controversy over the CV risk of febuxostat is ongoing. Meanwhile, two population-based retrospective cohort studies comparing the CV risk between allopurinol and benzbromarone showed different results. A retrospective cohort study using NHIS data between 2002 and 2017 found that benzbromarone may reduce CV risk and all-cause mortality by 22% and 66% compared to allopurinol [84]. In contrast, the other study did not find a significant difference in CV risk despite that the same NHIS database was used [85]. The conflicting results may be attributed to differences in data collection times and operational definitions of gout and outcomes. Considered together, it would be necessary to obtain information on various complications, including CV safety, with each ULT, and to prescribe drugs considering these safety profiles in the future.

The HLA-B*58:01 allele is known to be associated with a markedly elevated risk for AHS. The HLA-B*58:01 is present in approximately 7%~12% of Korean population with CKD, which is relatively higher than that of 0.7% of Caucasian and Hispanics [86-88]. It was demonstrated HLA-B*58:01 screening test before allopurinol imitation could considerably reduce the occurrence of AHS in Korean gout patients with CKD [88,89]. Also, 2020 American College of Rheumatology gout clinical practice guidelines conditionally recommended that, in subgroups of African and Southeast Asian ethnicities including Korean populations, HLA-B*58:01 tests should be performed to prevent AHS before starting allopurinol [90]. These will be included in the Korean College of Rheumatology guidelines for the management of gout in the future. Considering the increasing risk for AHS, and the higher prevalence of HLA-B*58:01 in Koreans with CKD, febuxostat might be positioned as a good alternative to replace allopurinol in Korea. However, the safety of febuxostat in gout patients with moderate-to-severe renal impairment has not been established. To answer these questions, there are two studies comparing the efficacy and tolerability of febuxostat in gout patients with CKD. Febuxostat was reported to be efficacious and well-tolerated in CKD in not only stage 3, but also in stage 4/5 patients [91]. After treatment with febuxostat for more than three months in Korean patients with gout on dialysis, the safety and effectiveness of febuxostat were acceptable [92]. In gout patients with CKD, an optimal treatment might be expected using the HLA-B*58:01 test and febuxostat.