Gout in China

Abstract

Gout is a common inflammatory joint disease in China. In recent years, the prevalence of gout in China has been increasing and the onset age of gout has been trending younger. The common risk factors for gout in China include hyperuricemia, age, sex, obesity, hypertension, metabolic syndrome, use of drugs (e.g., diuretics), dietary factors, chronic kidney disease (CKD), ethnicity, and income. Chinese clinical guidelines recommend the diagnosis of subclinical gout, refractory gout, and clinical classification of hyperuricemia in gout patients with early-onset or family history. Maintaining a consistently low level of serum urate is crucial for the effective long-term treatment of gout. However, the Chinese guidelines recommend paying special attention to allopurinol hypersensitivity when considering urate-lowering drugs. The adherence rate to urate-lowering therapy (ULT) in Chinese patients with gout ranges from 9.6% to 40.7%. Patient education and reducing drug side effects are effective approaches to improve the adherence to ULT and the rate of achieving the target urate level. The development of new treatment principles based on clinical trials, such as ULT based on the classification of hyperuricemia and urine alkalization, is recommended to improve patient outcomes and reduce potential side effects. The study of genetics, metabolites, and intestinal microbiota has yielded new findings that may aid in the diagnosis, classification, and pathogenesis of gout in China.

1. Introduction

Gout is one of the most common arthritic diseases worldwide. Reports indicate a broad global prevalence of gout ranging from less than 1% to 6.8% with an incidence rate between 0.6 and 2.9 per 1000 person-years [1]. Gout is caused by the innate immune response to deposited monosodium urate (MSU) crystals in the joints as a result of purine metabolism disorder and/or reduced urate excretion [2]. Hyperuricemia is the primary risk factor for gout. Gout can not only result in joint damage but also can present with other disorders, including metabolic syndrome and cardiovascular and renal diseases, and it is also an independent risk factor for cardiovascular complications [1]. Gout is a growing global public health concern.

In China, a cross-sectional survey conducted during 2015–2017 showed that the prevalence of gout in adults was 3.2% [3]. Although China does not have the highest prevalence of gout in the world, it has the largest number of gout incident cases in the world due to its large population. In 2019, China reported 0.4 million incident gout cases, which constituted 29.1% of the worldwide incident gout cases [4]. In recent years, the prevalence of gout in China has risen and the age of onset of gout has become younger [5,6]. Here we review the epidemiology, diagnosis, data on ULT and adherence, and pathogenic mechanisms over the past 10 years to provide direction for future research, diagnosis, and treatment of gout in China.

2. Epidemiology

2.1. The Prevalence and Incidence of Gout in China

The prevalence of gout in China has been increasing over the years, increasing from 1.1% in 2000–2014 to 3.2% in 2015–2017 [3,6], and 1.6% to 2.9% from 2006 to 2016 in Hong Kong [7]. The prevalence of gout in China increased at an alarming rate from 1990 to 2019 where the age-standardized prevalence rate for men and women was 12.3% and 3.9%, respectively [8]. The incidence rate of gout in the Taiwan region of China rose from 75.52 per 100,000 individuals (95% UI: 54.17–104.64) in 1990 to 110.06 per 100,000 individuals (95% UI: 79.37–151.06) in 2019 [4]. From 1990 to 2017, the prevalence and incidence of gout in China increased by 6.9% and 6.2%, respectively [9]. While the prevalence of gout has been on the rise both worldwide and in China, the magnitude of the increase among men in China (7.1%) has exceeded the global average (5.8%) [9]. The prevalence of gout in China is summarized in

Table 1. The Prevalence of gout in China.

Prevalence	Age	Data Collection Period	Setting	Study
1.1% (95% CI: 0.7%, 1.5%)	All ages	2000–2014	Meta-analysis in Mainland China	Liu et al. [6]
1.7 and 0.5% for male and female; 1.3 and 1.0% for inland and coast; 1.4, 1.0 and 0.7% for urban, city, and rural areas; 1.0 and 1.6% for community and hospital; 1.2, 1.7, and 0.8% for eastern, central and western region; 1.0, 1.1 and 1.3% for 2000–2005, 2006–2009 and 2010–2016	All ages	2000–2016	Meta-analysis in Mainland China	Chen et al. [10]
3.2% (4.4% for males, 2.0% for females)	≥18	2015–2017	A cross-sectional survey in Mainland China	Song et al. [3]
1.1% (1.9% for males, 0.4% for females)	20–80	2004	A sample survey in the northern coastal cities	Miao et al. [11]
12.3‰ and 3.9‰ for men and women (age-standardized)	15–89	2019	A joinpoint and age-period-cohort analysis	Zhu et al. [8]
3.6% (8.3%postmenopausal females, 1.3% postmenopausal women)	≥18	2015–2017	A cross-sectional and population-based study in Mainland China	Lu et al. [12]
Early onset gout: from 11.7% to 23.7% in 2008-2012 to 2013–2018	≤30	2008–2018	A 10-year observational study	Gao et al. [5]
10.42% in Taiwan aborigines, 2.98% in Taiwan Han	≥20	2006	A population-based cross-sectional study in Taiwan	Tu et al. [13]
1.56% to 2.92%	All ages	2006–2016	Hong Kong Gout Epidemiology Study	Tsoi et al. [7]

Study Miao et al. was included in the meta-study Song et al.

.

Gout has become more prevalent among younger people worldwide in recent years [4], and this trend is also observed in China [5,6]. Gao et al. found that, compared to 2008–2012, the proportion of early-onset gout (onset age ≤30 years old) in China increased from 11.7% to 23.7% in 2013–2018 and the mean age of onset decreased by 4.14 years [5]. Kuo et al. observed a secondary surge in gout incidence among individuals aged 30 to 39, indicating an emerging pattern of the disease manifesting at a younger age in Taiwan [14].

In China, the prevalence of gout varies by gender, age, region, and ethnicity. In adults, both in men and women, the occurrence of gout shows a positive correlation with age [8]. The prevalence of gout in mainland China was 1.7% among men and 0.5% among women, and the overall prevalence was 1.3% which was higher than in the coastal area (1.0%) [11]. A cross-sectional study showed that postmenopausal women were more likely to suffer from gout, with a prevalence of 3.6%, while the premenopausal prevalence of gout was 1.3% [12]. The prevalence of gout was higher in Taiwan aborigines with a prevalence of 10.4% in 2006 compared with 3.0% among the local Han Chinese [13], which may be due to the underlying genetic susceptibility of the Taiwan aboriginal population [15].

A study in northwestern China showed a significant difference in serum urate levels in Han Chinese, Uyghurs, and Kazakhs, among which the average serum urate level of Han Chinese was the highest (15.4%) and that of Uyghurs was the lowest (4.6%) [16]. In 2019, a study reported that the prevalence of hyperuricemia (serum urate level >360 µmol/L in females and >420 µmol/L in males) in the Bai nationality was 24.8% overall, significantly higher than that in other populations, and long-term exposure to high altitude areas plays an important role to polycythemia that may cause hyperuricemia [17].

2.2. Gout and Hyperuricemia in Adolescents

Several publications show that adolescent-onset gout is not uncommon in China. In the southern region of China, there were 111 adolescent-onset gout patients (age of onset ≤18 years) between 2016 and 2020 in Guangdong [18]. In the Taiwan region, 1.9% of gout patients were adolescents (age of onset ≤19 years) during the period of 1983 to 1999 [19]. However, in other countries, gout is very rare in adolescents. Based on research by Mikuls et al., utilizing the UK General Practice Research Database from 1990 to 1999, the incidence of gout in individuals under 25 years of age was 12 in 255,950 men and 1 in 246,346 women [20]. An analysis of a Japanese health insurance database revealed that the overall prevalence of gout among individuals aged 0 to 18 years was 0.040% (276 out of 696,277 patients) [21]. Between 2007 and 2015 in Korea, the incidence of gout ranged from 2 to 3 per 100,000 in the age group of 0–9 years, and from 9 to 20 per 100,000 in the age group of 10–19 years [22].

Multiple epidemiological surveys have shown that the prevalence of hyperuricemia in Chinese adolescents is significantly higher than that of adult males and has sharply increased [6,11,23,24,25,26,27]. A meta-analysis revealed that the total prevalence of hyperuricemia in children and adolescents at the age 3–19 years was 23.3%, with rates of 26.6% in males and 19.8% in females (sUA > 420 μmol/L in males and >360 μmol/L in females) [28]. The prevalence of hyperuricemia in adolescents varies among different populations and regions of China. In the eastern coastal area of China during 2017–2018, a cross-sectional study of 9371 adolescents aged 13 to 19 showed that the overall prevalence of hyperuricemia was 25.4%, with 42.3% among males and 8.0% among females (sUA ≥ 420 μmol/L) [23]. The prevalence was higher in the northern regions compared to the southern regions (24.2% vs. 19.7%), and there was a notable increase from 16.7% in the period 2009–2015 to 24.8% in 2016–2019 [28]. A study involving 8807 people found that the prevalence of hyperuricemia among adolescents in Beijing was 26.4% (sUA > 416 μmol/L) [25], and a study of 509 adolescents aged 13–16 years in Yangzhou City was 36.9%, with 43.2% in males and 30.8% in females (sUA > 420 μmol/L in males and >360 μmol/L in females) [29]. The prevalence of hyperuricemia among 15-year-old males and females in Taiwan was 43.7% and 27.4%, respectively (sUA > 458 μmol/L in males and >393 μmol/L in females) [30], and 40.2% and 29.5% in indigenous adolescent (4–13 years old) females and males in Taiwan, respectively (sUA > 420 μmol/L in males and >360 μmol/L in females) [27]. The increasing prevalence of hyperuricemia in adolescents is the most likely reason for the continuous increase in incidence as well as the earlier onset of gout in China [5].

2.3. Gout Risk Factors

Common risk factors for gout in China include hyperuricemia, age, sex, obesity, hypertension, metabolic syndrome, use of drugs (e.g., diuretics), dietary factors, chronic kidney disease (CKD), ethnicity, and income [2,31] (

Table 2. Gout risk factors in China.

Gout Risk Factor	Description	Study
Age	The prevalence of gout increases linearly with age, and increasing age is independently associated with the development of gout in both men and women.	Song et al. [3]
Area of residence	Living in urban areas was an independent risk factor for gout in men after adjusting for related confounders.	Song et al. [3]
Ethnic groups	Among the five ethnic groups of Han, Tibetan, Zhuang, Uygur, and Hui; Han, Zhuang, and Uygur populations are all at a reduced risk for gout, while Tibetan populations are at an increased risk.	Song et al. [3]
Economic income	As men’s income increased, the prevalence of gout showed a U-shaped curve.	Song et al. [3]
Educational background	A high education level was an independent risk factor for gout in men.	Song et al. [3]
Smoking	The age- and sex-standardized prevalence rates of gout are significantly different in mainland China.	Song et al. [3]
BMI	For every 1 kg/m2 increase in BMI, the serum urate level increased by 5.10 times in men and 3.93 times in women.	Zhou et al. [32]
Comorbidities (Obesity, Hypertension, Fatty liver, Renal insufficiency, Cardiovascular, and Dyslipidaemia)	The risk of hyperuricemia increased significantly with overweight, obesity, and waist circumference. A cross-sectional study showed that 26% of gout patients had hypertension, 17.6% had renal insufficiency according to eGFR, 53% had fatty liver disease, and 10.3% had coronary heart disease. The most common comorbidities involved coronary artery disease (CAD) (10.3%), chronic kidney disease (10.1%), and hyperlipidemia (57, 8.7%).	Liu et al. [16]; Liang et al. [33]; Wu et al. [34]

). Gout is regularly accompanied by obesity, CKD, hypertension, type 2 diabetes, dyslipidaemias, cardiac diseases, and metabolic syndrome. The prevalence of gout increases linearly with age and increasing age is independently associated with the development of gout in both men and women [3]. The risk of hyperuricemia increases with being overweight or obese and having a larger waist circumference [16]; once BMI reaches 19.1 kg/m², there was a positive association between BMI and serum urate level (5.10-fold (4.44, 5.77) for men and 3.93-fold (3.42, 4.43) for women in serum urate levels) [32]. A cross-sectional study showed that 26% of gout patients had hypertension, 17.6% had renal insufficiency based on eGFR, 53% had fatty liver disease, and 10.3% had coronary heart disease [33]. The cumulative risk of congestive heart failure is higher in men and women with hyperuricemia than in their respective counterparts without hyperuricemia [34]. Among the five ethnic groups (Han, Tibetan, Zhuang, Uygur, and Hui), the Han, Zhuang, and Uygur populations are all at a reduced risk for gout, while Tibetan populations are at an increased risk, compared to the Han population [3]. A study conducted in a region with a high level of economic development in northwest China found that participants with higher fasting blood glucose levels also had higher serum urate levels [16]. As income increased, the prevalence of gout in men showed a U-shaped curve, reaching its lowest point at an annual income of 10,000–30,000 Chinese Yuan, and an annual income of more than 100,000 Chinese Yuan is an independent risk factor for gout in men [3]. A high education level was also an independent risk factor for gout in men [3].

3. Diagnosis

3.1. The Diagnosis of Gout in China

The diagnosis of gout in China is in accordance with the classification criteria or diagnostic rules for gout of 2015 classification criteria: an American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) collaborative initiative [35,36]. The entry requirement for gout classification is a minimum of one instance of swelling, pain, or soreness in a peripheral joint or bursa. Detecting MSU crystals within the synovial fluid of a symptomatic joint/bursa or within a tophus independently qualifies an individual for gout classification, eliminating the need for additional scoring. If no MSU crystals are observed, a cumulative score is assigned based on clinical symptoms, signs, and laboratory and imaging examination results. A score of ≥8 can be used to diagnose gout clinically, and a computer artificial intelligence-assisted system can be used for rapid diagnosis.

3.2. The Diagnosis of Subclinical Gout and Refractory Gout

The guideline for the diagnosis and management of hyperuricemia and gout in China (2019) [37], made by the Endocrinology Branch of the Chinese Medical Association, recommended for the first time the diagnosis of subclinical gout and refractory gout. Subclinical gout is defined as patients with asymptomatic hyperuricemia in whom MSU crystal deposition and/or gouty bone erosion are detected by joint ultrasound, dual-energy CT, or X-ray. Refractory gout refers to having at least one of the following three conditions: (1) serum urate ≥360 μmol/L after taking conventional ULT alone or in combination for a sufficient amount and duration; (2) ≥2 gout attacks per year after receiving standardized treatment; and (3) the presence of multiple and/or progressive tophi.

3.3. Hyperuricemia and Classification of Hyperuricemia

Hyperuricemia is defined as serum urate ≥420 μmol/L in adults (both male and female). Based on both 24-h urinary urate excretion (UUE) and urate fractional excretion (FEUA), hyperuricemia can now be classified as four subtypes: renal urate overload (ROL), renal urate underexcretion (RUE), combined, or renal normal subtypes [38]. Gout patients with early-onset or family history are recommended to undergo clinical classification of hyperuricemia [37]. Ascertainment of gout subtypes was established based on the 2015 ACR/EULAR gout classification criteria [35].

4. Treatment

Treatment of gout flares mainly includes anti-inflammatory treatment and ULT. Urine alkalization is also recommended in China, especially in patients with CKD, patients receiving uricosuric treatment, and patients with urate kidney stones [39].

4.1. Anti-Inflammatory Treatment

The basis of treating gout flares lies in the swift and efficient management of the acute inflammation response. The anti-inflammatory and analgesic treatment for acute gout attacks in China is according to the recommendations of 2016 EULAR guidelines [40]. Colchicine and non-steroidal anti-inflammatory drugs (NSAIDs) are the first-line drugs for acute gout attacks. Corticosteroids are also recommended as the first-line anti-inflammatory and analgesic drugs by European and American guidelines [41]. However, the Chinese guidelines [37] recommend using corticosteroids as second-line analgesics and are only used to treat an acute gout attack when it involves multiple joints or large joints to prevent the abuse and repeated use of hormones, as overuse of glucocorticoid is a risk factor for ulceration over tophi and there is an association between severe tophaceous gout and glucocorticoid use [42,43].

For severe acute gout attacks (pain visual analog score (VAS) ≥ 7), polyarthritis, or those involving ≥2 large joints, it is recommended to use two or more analgesics [41], including colchicine and NSAIDs, colchicine, and combined use of oral corticosteroids, and intra-articular corticosteroid injections in combination with any other modality.

4.2. Serum Urate Management

4.2.1. ULT

Maintaining a consistently low serum urate level is crucial for the extended management of gout. Reducing serum urate levels to below saturation point (less than 357 μmol/L) through ULT results in the dissolution of MSU crystals, halts the progression of joint damage, reduces the occurrence of gout attacks, and enhances overall joint function [44]. ULT is prescribed to most patients to lower serum urate level to the target urate concentration of <357 μmol/L or at a lower target of <297.5 μmol/L for patients with tophaceous gout. ULTs can be categorized by their mechanisms of action, including inhibitors of urate production (for example, xanthine oxidase inhibitors), inhibitors of renal urate transport (uricosuric agents), and urate-metabolizing enzymes (such as pegloticase, a recombinant uricase). These classifications are in accordance with the 2019 Chinese guidelines for diagnosing and treating hyperuricemia and gout [37], which suggests (1) allopurinol, febuxostat, or benzbromarone are recommended as the first-line medication for ULT in gout patients; (2) allopurinol or benzbromarone is recommended as the first-line medication for ULT in asymptomatic hyperuricemia patients; and (3) patients whose serum urate levels have not reached the target after monotherapy with adequate dosage and course can consider combining urate-lowering drugs with different mechanisms of action. It is not recommended to use urate oxidase in combination with other urate-lowering drugs.

Most guidelines from Europe and America recommend allopurinol as a first-line ULT in patients with hyperuricemia and gout. It is recommended to start at a low dose and adjust the starting dose, incrementally increasing the maximum dose according to renal function. However, allopurinol hypersensitivity should be taken into consideration in Chinese people due to the higher incidence of hypersensitivity (prevalence of 2.7% in Taiwan, China [45]). There is a significant correlation between the occurrence of allopurinol hypersensitivity reaction and HLA-B*58:01, and the frequency of carriage of this allele in the Han Chinese population is 10% to 20% [46]. Based on a cost-benefit analysis, HLA-B*58:01 screening should be conducted before using allopurinol in the Chinese population, especially for people with hyperuricemia and gout with eGFR < 60mL·min⁻¹·(1.73 m²)⁻¹ [47]. European and American guidelines often recommend febuxostat as an alternative to allopurinol, and it should only be used when allopurinol is intolerant or has poor efficacy. However, as the price of febuxostat decreases and there is little evidence of increased risk of sudden cardiac death due to febuxostat usage in Asian populations, febuxostat was recommended as the first-line urate-lowering drug for gout patients in China. Additionally, the European guidelines often recommend benzbromarone as the second-line drug because of concerns raised by hepatotoxicity reports [48,49].

The decision to begin ULT amidst an acute gout attack remains a subject of debate. The 2020 ACR guidelines for gout suggest a conditional endorsement for initiating ULT during a gout flare [50]. One study assessed the effectiveness and safety profile of initiating febuxostat during an acute gout episode. This evaluation was based on a 12-week prospective, randomized controlled trial involving primary gout patients hospitalized due to acute gout attacks [51]. The findings from this study indicated that starting treatment with febuxostat at the onset of an acute gout flare-up did not result in any notable changes in terms of daily pain levels, frequency of subsequent flares, or the occurrence of side effects, suggesting that early treatment with a urate-lowering drug could offer enduring advantages for gout patients. Another study showed that ULT resulted in a decrease in serum urate level accompanied by a decrease in visceral fat area; this observation lays the groundwork for future clinical studies to confirm if initiating ULT contributes to the reduction of visceral fat among people with gout [52].

4.2.2. Adherence to ULT

Noncompliance with ULT is a frequent and challenging issue in the treatment of gout, and poor adherence to ULT demonstrates a suboptimal gout care condition. A recent meta-analysis, which included data from 22 studies encompassing a total of 137,699 gout patients, found that the overall compliance rate for ULT stood at 47% (95% CI 42% to 52%) [53].

A study conducted in China assessed the use of ULT among 1,588 primary gout patients and showed that 92.7% of the participants commenced ULT with 82.9% adhering for 3 months; however, adherence dropped to 63.5% at 6 months and 40.5% at 12 months. The impact of ULT was evident through a decrease in gout flares and improvements in both the patient global pain visual analog scale and health assessment questionnaire scores at month seven, but no further improvements were noted after month 13 [54]. Sheng et al. showed that ULT medication adherence was 21.9% among male patients as determined through telephone interviews [55] and found that 40.9% of patients who were prescribed ULT had not taken any ULT in the last 12 months. The authors identified several factors contributing to the lack of adherence to medication, including remission after treatment (35.3%), concerns about potential side effects (22.7%), lack of patient education (8.7%), adverse events (8.2%), and others. In a separate study, Li et al. examined 903 Chinese patients with gout, focusing on a 2-year medication possession ratio (MPR) where an MPR of ≥80% was considered high adherence. The study found significant correlations between high adherence and several factors: male gender (OR = 3.7), onset of gout at age >60 years (OR = 3.5), disease duration >5 years (OR = 1.7), presence of multiple comorbidities (OR = 1.7), detectable palpable tophi at baseline (OR = 1.5), SU levels <6 mg/dL (<360 µmol/L; OR = 1.9), and increased frequency of follow-up visits (OR = 2.0) [56]. The variance in compliance among Chinese patients with gout, compared to several studies from Western countries, underscores the necessity to avoid stereotyping gout patients for predicted nonadherence. Yin et al. assessed ULT adherence among Chinese gout patients amid the COVID-19 pandemic and discovered that ULT adherence rate was 22.8%, which is higher than the usual adherence rate of 9.6% observed during non-pandemic times [57]. In contrast to the group that adhered to treatment, patients with gout who did not follow their ULT regimen tended to have a shorter duration of flare symptoms, diminished confidence in managing their condition, less perceived need for the therapy, greater concerns regarding the therapy, and a narrower gap between the perceived necessity and concerns. Moreover, psychological factors such as depression and anxiety, along with concerns related to the COVID-19 pandemic (accounting for 27.7%), did not significantly influence adherence to ULT.

Patient education and reducing drug side effects are effective approaches to improve adherence to ULT and achieving urate targets, and the development of new treatment principles based on clinical trials are recommended in China, such as hyperuricemia classification-based ULT.

4.2.3. Hyperuricemia Classification-Based ULT

Based on both 24-h urinary urate excretion (UUE) and fractional excretion of uric acid (FEUA), hyperuricemia can be classified as four subtypes. The clinical and genetic features of each subtype were demonstrated in a cross-sectional study of 4873 gout patients in China. In total, 428 (8.8%) had the renal overload subtype, 2970 (60.9%) had the renal under excretion subtype, 1124 (23.1%) had the combined subtype, and 351 (7.2%) had the normal subtype [58]. In an observational study involving 428 patients with CKD, of which 218 had hyperuricemia, it was noted that as the CKD stages progressed, there was a marked increase in the percentage of patients classified under the normal subtype [59]. Early-onset patients (< 30 years old) had lower FEUA (4.4% vs. 7.2%, p < 0.05) compared to controls [60]. However, the cumbersome nature of collecting urine over a 24-h period and the stringent lifestyle restrictions impede its practicality for routine use. A prediction model for RUE composed of four single nucleotide polymorphisms (rs3775948 of SLC2A9/GLUT9, rs504915 of NRXN2/URAT1, rs2231142 of ABCG2, and rs11231463 of SLC22A9/OAT7) and seven readily accessible clinical features (age, hypertension, nephrolithiasis, blood glucose, serum urate, urea nitrogen, and creatinine) was established with acceptable accuracy (AUC of 0.90) [61].

Clinical evidence indicates that tailoring the choice of ULT agent to specific clinical subtypes may offer a more individualized method for managing gout. In a clinical trial comparing the effectiveness of low-dose benzbromarone with low-dose febuxostat in patients with gout who exhibit renal urate underexcretion, a greater number of participants in the benzbromarone group reached the desired serum urate levels compared to the febuxostat group (61% versus 32%, p < 0.001), while maintaining comparable safety profiles [62]. Another prospective study showed that in the combined subtype of gout (UUE > 600 mg/d/1.73m² and FEUA < 5.5%), febuxostat (20 mg) combined with benzbromarone (25 mg) per day was more effective than febuxostat alone (40 mg) (47.7% compared to 75.5%, p < 0.001) [63]. Additionally, individuals with the combined subtype of gout exhibited a diminished response to febuxostat in contrast to renal overload or renal underexcretion subtypes (45.5%, 64.8%, and 56.6% respectively, p < 0.05) [63]. Collectively, these findings indicate that the choice of ULT agent based on the underlying pathogenic cause of hyperuricemia could be advantageous. Nonetheless, whether the strategy of ULT selection based on clinical typing is universally applicable to all gout patients is not clear.

4.3. Urine Alkalization

Typically, urine pH is mildly acidic, with an average value around 6.0. Acidic urine occurs when the pH falls below 5.5 [64]. Acidic urine is an independent risk factor for a variety of metabolic conditions, such as non-alcoholic fatty liver disease, obesity, diabetes, and CKD [65,66,67,68,69,70]. In gout patients, urine pH value is affected by factors such as diet, insulin resistance, thiazide diuretics, and CKD drugs [71,72,73,74], and one study showed that the urine pH value of gout patients is significantly lower than that of controls (5.6 vs. 5.9) [75]. A Chinese population-based cross-sectional study has shown that nearly 50% of patients with gout have acidic urine [39]. The incidence of multiple kidney stones in gout patients with urine pH < 5.0 is as high as 16.5%, which is significantly higher (6.8%–8.7%) than in patients with urine pH > 5.0. A higher prevalence of kidney cysts was observed in patients with pH ≤ 5.0 (19.5%) than in patients with urine 5.0 < pH ≤ 6.9 (9.7%–13.1%). This indicates a markedly increased risk of kidney disease in individuals with a urine pH of 5.0 or lower compared to those with a pH between 6.2 and 6.9. Specifically, a urine pH of 5.0 or less is associated to a 1.6 times greater risk of stage 1 CKD, a 1.5 times greater risk of kidney stones, a 1.6 times greater risk of developing kidney cysts, and a 1.7 times greater risk of microhematuria in urine [39]. Due to the increased risks of these diseases, urine alkalization is recommended in China, especially in patients with CKD, patients receiving uricosuric treatment, and patients with urate kidney stones [37]. However, alkalinizing the urine is conditionally recommended against for patients with gout and hyperuricemia in the 2020 American College of Rheumatology Guideline due to lack of evidence, even for patients receiving uricosuric treatment [50].

The primary medications used to alkalize urine typically include sodium bicarbonate, potassium citrate, and a blend of citrates, each offering distinct benefits (

Table 3. The comparison of advantages of alkalizing urine drugs.

Alkalizing Urine Drugs	Advantages
Sodium bicarbonate	Suitable for patients with CKD complicated with metabolic acidosis
Potassium citrate	Dissolves urinary calculi
Potassium sodium hydrogen citrate mixture	Dissolves urate stones and calcium stones; Reduces the occurrence of urine occult blood and decreases the frequency of gout attacks
Tart cherry supplementary citrate mixture	More significant improvements in the urine albumin/creatinine ratio and C-reactive protein levels, indicating extra renal protective benefits and diminished inflammation in gout

). Sodium bicarbonate primarily regulates acid-base imbalances by elevating the levels of bicarbonate ions in the serum and is suitable for individuals with CKD and metabolic acidosis [76]. In clinical settings, potassium citrate is often the preferred medication for dissolving and preventing kidney stones caused by acidic urine [77]. A combination treatment of allopurinol and a mixture of citrates not only helps in making the urine more alkaline but also contributes to better kidney function [78]. A prospective, randomized, parallel-controlled trial in China showed no significant difference in the alkalizing effect of sodium bicarbonate and citric acid mixture on urine [79]. However, compared to sodium bicarbonate, the citrate mixture was safer, more tolerated, and was able to reduce the risk of gout attacks [79]. Following a 12-week period of urine alkalization, the incidence of occult blood in the urine was greater in the group treated with sodium bicarbonate compared to the citrate mixture group (38% vs 24%, p < 0.05). While the rate of kidney stone formation was comparable between the two groups, the citrate mixture group experienced significantly fewer number of people who had two gout flares (4% vs 12%, p = 0.037) [79].

Tart cherries are rich in anthocyanins, compounds known for their strong anti-inflammatory and antioxidant effects [80]. One study in China showed that a tart cherry-enhanced citrate mixture, referred to as TaCCi, was just as effective and safe in promoting urine alkalization and reducing serum urate levels as traditional citrate mixtures and sodium bicarbonate in gout patients. Notably, the TaCCi mixture improved urine albumin/creatinine ratio and C-reactive protein levels and may offer additional renal protective benefits and diminish inflammation in gout, especially during the initiation of ULT [81].

Whether alkaline urine can achieve multiple benefits in gout patients, the influence of alkaline urine on serum urate level, and whether citrate supplementation can increase the concentration of citric acid in body fluids and inhibit the formation of MSU crystals in tissues and prevent gout attacks remain unclear.

5. Mechanisms

5.1. Studies on the Genetics of Gout

Genetic influences are important in the onset of hyperuricemia and the progression to gout. Genome-wide association studies (GWAS) in serum urate levels have confirmed the genetic variants of the strongest effect to map within genes that encode kidney and gut urate transporters, specifically ABCG2, URAT1 (SLC22A12), and GLUT9 (SLC2A9) [82]. Recent GWAS in gout have confirmed the importance of genetic control of serum urate levels in addition to revealing new pathways in the inflammatory process of gout [83]. However, systematic approaches to identifying the genetic basis for gout and hyperuricemia have been heavily biased toward populations of European ancestry. The Chinese population was included in the East Asian cohort of the largest GWAS of gout [84].

In the Chinese population, two urate-associated genetic variants were confirmed: one in SLC2A9 (rs11722228, p = 8.98 × 10⁻³¹) and another in ABCG2 (rs2231142, p = 3.34 × 10⁻⁴²) [85,86]. A GWAS involving 1255 Han Chinese individuals with gout identified correlations with three novel genetic loci (BCAS3, RFX3, and KCNQ1) [84]. The BCAS3 locus was also reported in a GWAS in European participants for serum urate concentrations [87] and showed a significant association with gout in the Japanese population (p = 1.66 × 10⁻³; odds ratio (OR) = 0.80) [88]. Beyond the genes ABCG2 and SLC2A9, key genetic contributors to gout and asymptomatic hyperuricemia, a GWAS in the Chinese population revealed significant gout associations with variants on chromosome 1, including rs2974935 (MTX1), rs4971100 (TRIM46), rs10927807 (AGMAT), rs4072037 (MUC1), rs9286836 (NUDT17), and rs7546668 (DNAJC16) [89]. The SLC28A2 gene showed associations with serum urate in Han Chinese [90]. GCKR, that regulates the activity of the glucose metabolizing enzyme glucokinase, was associated with gout not only in Chinese populations [91,92], but also in Polynesian, European, and Japanese populations [93,94,95].

Whole-genome sequencing was performed on an adolescent-onset gout cohort to investigate genetic variants associated with early-onset gout, with the previously published gene ABCG2 associated with early-onset gout being detected, and a new locus at RCOR1, where functional analysis supported the role of RCOR1 in the inflammatory mechanism [96]. A GWAS conducted using data from the Taiwan biobank identified six genetic variants in the SLC2A9, C5orf22, CNTNAP2, and GLRX5 genes as significant predictors of gout in women aged ≥50 [97]. In addition to SNPs, copy number variation may also play a role in the development of gout. Copy number variations of three genes, ABCF1, IL17REL, and FCGR3A were identified as being associated with the risk of gout [98]. Even though there have been many studies published on the genetics of gout in the Chinese population, there is still a lack of large-sample cohort studies equivalent to those in the European population.

5.2. Studies on Metabolomics in Gout

Metabolites, in contrast to genetic variants, directly reflect biochemical processes and are shaped by a variety of factors, including genetics and environmental influences [99]. Several studies revealed that metabolites can serve as biomarkers in gout, capable of discerning the various phases of disease evolution. The biomarkers that have been identified could potentially mediate the association among hyperuricemia, gout and kidney disease, metabolic syndrome, and hypertriglyceridemia (Table 4). More than 30 studies regarding metabolites of gout have been performed in China, reviewed in [100,101].

5.2.1. Serum Metabolomics

Metabolomics has been used to differentiate gout, hyperuricemia, and healthy controls [102,103,104,105]. Systematic metabolic alterations were identified by metabolomics in previous studies: arginine and proline metabolism, taurine and hypotaurine metabolism, alanine, aspartate, and glutamate metabolism altered in hyperuricemic patients; and arginine biosynthesis, glycine, serine, and threonine metabolism altered in gout [105]. In one study conducted by Shen et al., seven metabolites including sphingomyelin, trigonelline, pyroglutamic acid, citrulline, inositol, arachidonate, and glycocholate differentiated hyperuricemia from healthy controls and four metabolites including glutamate, pyroglutamic acid, glycocholate, and lactic acid distinguished patients with gout from healthy controls, and seven metabolites including uracil, trigonelline, betaine, pipecolic acid, myristic acid, arachidonate, and glycocholate distinguished patients with gout from hyperuricemia [105]. In other studies, pyroglutamic acid, 2-methylbutyryl carnitine, and Phe-Phe were reported as potential gout biomarkers [104], and lactic acid, valine, tyrosine, phenylalanine, arachidonic acid, stearic acid, linoleic acid, palmitic acid, oleic acid, lysoPC(18:0), lysoPC(16:0), and lysoPC(18:1(9Z)) as biomarkers of hyperuricemia [102].

Metabolomics can also be used in investigating metabolic profiles regarding different stages of gout [106,107]. Kang et al. revealed a significant elevation in hypoxanthine levels among patients with chronic gout [106]. This finding suggests that hypoxanthine could serve as a potential biomarker for identifying individuals with chronic gout, differentiating them from patients at various other stages. Additionally, they observed that patients with gouty nephropathy exhibited notably increased levels of creatinine. Lyu et al. verified that kynurenic acid (KYNA) and 5-hydroxyindoleacetic acid (5-HIAA) are associated with acute inflammatory responses [107]. In contrast, pyridinoline (2PY) and 2-aminoimidazole (2AMIA) are indicators of renal function impairment resulting from long-term hyperuricemia. Therefore, these four metabolites may be recognized as biomarkers indicative of the developmental stages in the progression of gout [107]. Furthermore, one prospective study based on 1621 community-dwelling Chinese participants identified that nine metabolites (cysteine, glutamine, phenylalanine, threonine, and long-chain acylcarnitines C14:1OH, C18, C18:2, C20, and C20:4) were significantly associated with urate level [106].

The metabolic profile of acute gout patients showed an increased level of leukotriene B4 (LTB4) and the increase of LTB4 was accounted for by the dynamic balance between the activation of 5-lipoxygenase and CYP4F3 [108]. Furthermore, Wang et al. discovered a distinct metabolomic profile in frequent gout flare and infrequent gout flare, where the crosstalk of purine metabolism, caffeine metabolism, taurine metabolism, and bile acid metabolism associate with frequent gout flares. Using six metabolites, including 4-trimethyl-ammioniobutanoic acid, 5′-methylthioadenosine, arachidic acid, taurine, uridine, and xanthine, Wang et al. constructed predictive models in multiple machine learning algorithms where the area under the curve (AUC) reached 0.88. Metabolites of organic acids, lipids, steroids, hormones, and transmitters were downregulated while carbohydrates were upregulated in gout patients with frequent flares [109].

5.2.2. Non-Serum Metabolomics

Samples including urine and saliva were also used for metabolic profiling of gout patients. Three separate studies focusing on urine metabolomics identified amino acids, carbohydrates, organic acids, and related compounds [110,111,112]. These metabolites are linked to disruptions in processes such as purine nucleotide synthesis, amino acid and purine metabolism, lipid and carbohydrate metabolism, as well as the tricarboxylic acid cycle. Notably, urate was detected in all three studies, and when combined with isoxanthopterin, it serves as an effective means to distinguish gout patients from non-affected individuals, achieving an AUC value of 0.88. An alternative investigation utilizing saliva identified three metabolic markers: urate, oxalic acid, and L-homocysteic acid. The receiver operating characteristic analysis indicated that these metabolites could effectively separate gout patients from those with hyperuricemia, exhibiting an AUC of 0.89, with specificity and sensitivity rates of 73.3% and 93.3%, respectively. Moreover, a combination of these three metabolites was able to accurately differentiate individuals with gout from healthy subjects [112].

5.2.3. Lipidomics

A prospective cohort analysis involving 1606 Chinese individuals with gout demonstrated a significant correlation with hyperlipidemia [113] and lipidomics was applied in the study of gout pathogenesis [114,115], where Liu et al. discovered TAG (18:1–20:0–22:1) and TAG (14:0–16:0-16:1) could serve as biomarkers to differentiate hyperuricemia from gout groups (AUC = 0.83). Wang et al. conducted an oxylipin (oxidation products of polyunsaturated fatty acids (PUFAs)) profile examination and identified 14(S)-HDHA (14S-hydroxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid) as the common metabolite in both comparisons (gout vs hyperuricemia and gout vs health controls). Diagnostic models were developed using oxylipins, where solely 14(S)-HDHA exhibited an AUC of 1 (95% CI, 1, 1) in both comparative analyses [116].

Table 4. Biomarkers identified by metabolomics.

Biomarkers	Description	Sample	Patients/Reference	Study
Betaine, trigonelline, glycocholate; uracil; pipecolic acid; myristic acid; arachidonate	Biomarkers discriminating gout from hyperuricemia	Serum	Total of 330 patients: healthy controls (n = 119), gout patients (n = 109) and hyperuricemia patients (n = 102)	Shen et al. [105]
Xanthine, uridine, taurine, arachidic acid, 5′-methylthio adenosine, 4-trimethyl ammonio butanoic acid	Biomarkers distinguishing frequent and infrequent gout	Serum	Total of 638 patients: 163 infrequent gout and 239 frequent gout patients in the discovery cohort; 97 infrequent gout and 139 frequent gout patients in the validation cohort	Wang et al. [109]
Urate, creatinine, tryptophan, guanosine and hippurate	Biomarkers distinguishing gout and acute gout	Serum and urine	Serum samples: 21 gout patients and 21 age-matched normal males; urine samples: 19 gout patients and 20 non-gout subjects	Liu et al. [111]
Urate, oxalic acid, and L-homocysteic acid (HCA)	Biomarkers distinguishing gout and hyperuricemic patients	Salivary	Total of 128 participants: the discovery stage included 38 individuals and the validation stage included 90 individual	Cui et al. [112]
Hypoxanthine	Elevated level of hypoxanthine in chronic gout patients	Serum	Total of 65 patients: 15 healthy controls, 15 acute gout patients, 10 intermittent gout patients, 10 chronic gout patients, and 15 gouty nephropathy patients	Kang et al. [106]
KYNA,5-HIAA, 2PY, and 2AMIA	Biomarkers associated with an acute inflammatory response in gout or renal impairment resulting from prolonged hyperuricemia.	Serum	Total of 547 participants: training dataset 347 subjects and validation cohort 200	Lyu et al. [107]
TAG 18:1–20:0–22:1 and TAG 14:0–16:0–16:1	Biomarkers distinguishing hyperuricemic and gout patients	Serum	Total of 428 participants: 157 HUA, 183 gout, and 88 normal controls	Liu et al. [115]

Table 4. Biomarkers identified by metabolomics.

Biomarkers	Description	Sample	Patients/Reference	Study
Betaine, trigonelline, glycocholate; uracil; pipecolic acid; myristic acid; arachidonate	Biomarkers discriminating gout from hyperuricemia	Serum	Total of 330 patients: healthy controls (n = 119), gout patients (n = 109) and hyperuricemia patients (n = 102)	Shen et al. [105]
Xanthine, uridine, taurine, arachidic acid, 5′-methylthio adenosine, 4-trimethyl ammonio butanoic acid	Biomarkers distinguishing frequent and infrequent gout	Serum	Total of 638 patients: 163 infrequent gout and 239 frequent gout patients in the discovery cohort; 97 infrequent gout and 139 frequent gout patients in the validation cohort	Wang et al. [109]
Urate, creatinine, tryptophan, guanosine and hippurate	Biomarkers distinguishing gout and acute gout	Serum and urine	Serum samples: 21 gout patients and 21 age-matched normal males; urine samples: 19 gout patients and 20 non-gout subjects	Liu et al. [111]
Urate, oxalic acid, and L-homocysteic acid (HCA)	Biomarkers distinguishing gout and hyperuricemic patients	Salivary	Total of 128 participants: the discovery stage included 38 individuals and the validation stage included 90 individual	Cui et al. [112]
Hypoxanthine	Elevated level of hypoxanthine in chronic gout patients	Serum	Total of 65 patients: 15 healthy controls, 15 acute gout patients, 10 intermittent gout patients, 10 chronic gout patients, and 15 gouty nephropathy patients	Kang et al. [106]
KYNA,5-HIAA, 2PY, and 2AMIA	Biomarkers associated with an acute inflammatory response in gout or renal impairment resulting from prolonged hyperuricemia.	Serum	Total of 547 participants: training dataset 347 subjects and validation cohort 200	Lyu et al. [107]
TAG 18:1–20:0–22:1 and TAG 14:0–16:0–16:1	Biomarkers distinguishing hyperuricemic and gout patients	Serum	Total of 428 participants: 157 HUA, 183 gout, and 88 normal controls	Liu et al. [115]

5.3. Studies on Gut Microbiota in Gout

Gout is caused by an increased serum urate level and inflammatory response to MSU crystals. Seventy percent of urate in the human body is excreted by the kidneys, and the remaining 30% is excreted by the intestines [117]. Gut dysbiosis associates with dysregulated host uric acid degradation and systemic inflammation in gout [118]. The gut microbiome is influenced by many factors, including diet, environment, and geographical location [119,120]. Table 5 summarizes the studies that link the gut microbiota with gout and hyperuricemia in the Chinese population.

A metagenomic study of 307 fecal samples from 102 individuals with gout and 86 healthy controls was conducted and discovered that Prevotella, Fusobacterium, and Bacteroides were elevated in those with gout, while the levels of Enterobacteriaceae and butyrate-producing bacteria were diminished [118]. Chen et al. found significant changes in the gut bacteriome, mycobiome, and virome of patients with gouty arthritis [121]. A cohort study found hyperuricemic individuals had a lower relative abundance of Coprococcus compared to those with normouricemic individuals [122]. Lin et al. discovered that a reduction in the diversity of gut microbiota was observed in patients with gout who had not received ULT treatment [123]. Xing et al. discovered primary gout associated with the change of diversity and similarity in both Bacteroides and Clostridium [124]. An analysis of the microbiome and metabolome indicated an increased presence of opportunistic pathogens, including Bacteroides, Porphyromonadaceae Rhodococcus, Erysipelatoclostridium, and Anaerolineaceae, in gout patients [125].

Functional analysis indicates that the gut microbiome in individuals with gout shows enhanced activity in carbohydrate metabolism yet demonstrates a diminished capability for purine metabolism [123]. Guo and Gong et al. found the microbiota encoding the allantoinase gene that degrades urate into allantoin was lacking in gout patients, but the microbiota that express the xanthine oxidase gene was enriched [126,127]. Xanthine oxidase can convert hypoxanthine and xanthine to urate. In gout patients, the Bacteroides and Prevotella species are more predominant than Enterobacteriaceae, which might lead to a modification in the biosynthesis process from six-acyl-chain lipid A to four- or five-acyl chain lipid A, which could potentially have adverse impacts on the host immune response and tolerance to endotoxins [118]. The reduction in Enterobacteriaceae species could lead to impaired urate degradation, resulting in heightened systemic accumulation of urate and subsequent inflammatory responses in gout [118]. The species of gut microbiota that produce short-chain fatty acids (SCFAs) have a protective function in inflammation and are increased in abundance in the healthy group [128]. Microbial functions like SCFA production and the assembly of flagella could play a role in preserving a balanced gut microenvironment. A decrease in these functions in gout patients might lead to heightened inflammation, both locally and systemically, by altering their corresponding host receptors [118].

Table 5. The studies of gut microbiota with gout and hyperuricemia in the Chinese population.

Description	Sample	Sequence Method	Patients/Reference	Study
Prevotella, Fusobacterium, and Bacteroides were elevated in those with gout, while the levels of Enterobacteriaceae and butyrate-producing bacteria were diminished	Fecal samples	Metagenomic sequencing	102 individuals with gout and 86 healthy controls	Chu et al. [118]
Significant changes in the gut bacteriome, mycobiome, and virome of patients with gouty arthritis	Fecal samples	Whole-metagenome shotgun sequencing	26 gout patients and 28 healthy controls	Chen et al. [121]
Hyperuricemic individuals had a lower relative abundance of Coprococcus compared to those with normouricemic individuals	Fecal samples	16S ribosomal RNA sequencing	1,392 subjects (17.2% with hyperuricemia) and 480 subjects for validation (240 with hyperuricemia)	Wei et al. [122]
A restriction of gut microbiota biodiversity was detected in the untreated gout patients, and the alteration was partly restored by febuxostat.	Fecal samples	16S ribosomal RNA sequencing and metagenomic shotgun sequencing	38 gout patients treated with febuxostat, and 26 healthy controls	Lin et al. [123]
Primary gout associates with the change of diversity and similarity in both Bacteroides and Clostridium.	Fecal samples	16S ribosomal RNA sequencing	90 gout patients and 94 healthy controls	Xing et al. [124]
An increased presence of opportunistic pathogens, including Bacteroides, Porphyromonadaceae Rhodococcus, Erysipelatoclostridium, and Anaerolineaceae in gout patients	Fecal samples	16S rRNA Gene Tag Sequencing	26 gout patients and 26 healthy controls	Shao et al. [125]
In gout, Bacteroides caccae and Bacteroides xylanisolvens are enriched yet Faecalibacterium prausnitzii and Bifidobacterium pseudocatenulatum depleted	Fecal samples	16S rRNA genes V1-V3 region and pyrosequencing	35 gout patients and 33 healthy controls	Guo et al. [127]
The gut bacterial diversity in the hyperuricemic group reduced significantly and the community of the microbiota was of significant difference between the two groups	Fecal samples	Whole-genome shotgun sequencing	69 patients with HUA and 118 healthy controls	Sheng et al. [128]
A number of bacterial species, such as unidentified Enterobacteriaceae, Roseburia, and Faecalibacte-rium, exhibit significant diagnostic potential for identifying asymptomatic hyperuricemia	Fecal samples	16S rRNA gene sequencing	45 asymptomatic hyperuricemia and 45 healthy controls	Yang et al. [129]

Table 5. The studies of gut microbiota with gout and hyperuricemia in the Chinese population.

Description	Sample	Sequence Method	Patients/Reference	Study
Prevotella, Fusobacterium, and Bacteroides were elevated in those with gout, while the levels of Enterobacteriaceae and butyrate-producing bacteria were diminished	Fecal samples	Metagenomic sequencing	102 individuals with gout and 86 healthy controls	Chu et al. [118]
Significant changes in the gut bacteriome, mycobiome, and virome of patients with gouty arthritis	Fecal samples	Whole-metagenome shotgun sequencing	26 gout patients and 28 healthy controls	Chen et al. [121]
Hyperuricemic individuals had a lower relative abundance of Coprococcus compared to those with normouricemic individuals	Fecal samples	16S ribosomal RNA sequencing	1,392 subjects (17.2% with hyperuricemia) and 480 subjects for validation (240 with hyperuricemia)	Wei et al. [122]
A restriction of gut microbiota biodiversity was detected in the untreated gout patients, and the alteration was partly restored by febuxostat.	Fecal samples	16S ribosomal RNA sequencing and metagenomic shotgun sequencing	38 gout patients treated with febuxostat, and 26 healthy controls	Lin et al. [123]
Primary gout associates with the change of diversity and similarity in both Bacteroides and Clostridium.	Fecal samples	16S ribosomal RNA sequencing	90 gout patients and 94 healthy controls	Xing et al. [124]
An increased presence of opportunistic pathogens, including Bacteroides, Porphyromonadaceae Rhodococcus, Erysipelatoclostridium, and Anaerolineaceae in gout patients	Fecal samples	16S rRNA Gene Tag Sequencing	26 gout patients and 26 healthy controls	Shao et al. [125]
In gout, Bacteroides caccae and Bacteroides xylanisolvens are enriched yet Faecalibacterium prausnitzii and Bifidobacterium pseudocatenulatum depleted	Fecal samples	16S rRNA genes V1-V3 region and pyrosequencing	35 gout patients and 33 healthy controls	Guo et al. [127]
The gut bacterial diversity in the hyperuricemic group reduced significantly and the community of the microbiota was of significant difference between the two groups	Fecal samples	Whole-genome shotgun sequencing	69 patients with HUA and 118 healthy controls	Sheng et al. [128]
A number of bacterial species, such as unidentified Enterobacteriaceae, Roseburia, and Faecalibacte-rium, exhibit significant diagnostic potential for identifying asymptomatic hyperuricemia	Fecal samples	16S rRNA gene sequencing	45 asymptomatic hyperuricemia and 45 healthy controls	Yang et al. [129]

The alterations of the gut microbiota were observed after ULT and suggest that ULT has anti-inflammatory effects that could lead to a partial reinstatement of gut microbiota in individuals with gout after a treatment period of 24 weeks [118]. Treatment with febuxostat may partially rectify the imbalance in the gut microbiota of gout patients by enhancing purine metabolism [123].

Gut microbiota may be used as diagnostic markers for gout or disease remission. A predictive model constructed on three specific genes (gene ID: 415936 (N-6 DNA methylase), 15049 (exo-alpha-sialidase), and 1697136 (relaxase/mobilization nuclease domain-containing protein)) from the gut microbiota demonstrated high accuracy in predicting gout, achieving an AUC of 0.91 in the discovery cohort and 0.80 in the validation cohort, and it also showed high specificity even when other chronic conditions were considered [118]. A classification approach that utilized significantly enriched bacterial genera distinguishing healthy individuals from those with gout achieved a high average AUC of 0.97 in the ROC analysis, showcasing strong potential in accurately identifying gout [123]. A cohort study in China developed a diagnostic model predicated on 17 types of bacteria associated with gout, achieving an accuracy of 88.9% [127]. Furthermore, a number of bacterial species, such as unidentified Enterobacteriaceae, Roseburia, and Faecalibacte-rium, exhibit significant diagnostic potential for identifying asymptomatic hyperuricemia [129]. Therefore, the special characteristics of the gut microbiota from gout and hyperuricemia may be a non-invasive diagnostic tool and may offer a potential focus for future preventative measures and treatments in China.

6. Conclusions

The prevalence of gout in China has been increasing and the onset age of gout has been trending younger in recent years, which deserves our attention. When using urate-lowering drugs, people in China (and in other East Asian countries) should pay attention to genetic differences with European people. Two studies suggest that ULT based on hyperuricemia classification is more effective and can increase adherence to ULT in the Chinese population. The difference in ULT adherence rates ranged from 9.6% to 40.7%, indicating that improving gout management in China remains an important future task. The studies on genetics, metabolomics, and intestinal flora have revealed part of the pathogenesis of gout in China, which may help with non-invasive diagnosis and precise treatment in the future.

• Key Points

  ➢

  The prevalence of gout in China has been increasing and the onset age of gout has been trending younger in recent years, which should be taken seriously. Adolescent-onset gout is common in China, while it is very rare in other countries according to the current surveys.

  ➢

  The Chinese clinical guidelines recommend the diagnosis of subclinical gout, refractory gout, and clinical classification of hyperuricemia in gout patients with early-onset or family history.

  ➢

  The treatment of gout flares mainly includes anti-inflammatory treatment and ULT. ULT based on the classification of hyperuricemia is recommended in China, which is more effective and can increase adherence to ULT. Due to the risk of acidic urine, urine alkalization is also recommended in China, especially in patients with CKD, patients receiving uricosuric treatment, and patients with uric acid kidney stones.

  ➢

  Genetic research has revealed new loci in the Chinese population, especially the identification of the adolescent-onset gout gene RCOR1, but there is still a lack of large-sample cohort studies. Both metabolites and the gut microbiota can serve as biomarkers for gout or biomarkers of disease remission.