2024 Update of Chinese Guidelines for Diagnosis and Treatment of Hyperuricemia and Gout Part I: Recommendations for General Patients

3.1. Urate‐Lowering Therapy in Asymptomatic Hyperuricemia

For patients with asymptomatic hyperuricemia, first‐line ULT options include febuxostat, allopurinol, and benzbromarone; long‐term ULT is generally recommended, with discontinuation considered for patients maintaining SU ≤ 360 μmol/L for three months or < 240 μmol/L on two separate occasions. The decision should involve lifestyle modification and regular SU monitoring.

Patients with asymptomatic hyperuricemia and SU ≥ 9 mg/dL, or those with comorbidities such as cardiovascular, metabolic dysfunction, and kidney diseases, should initiate ULT as per the 2019 Guideline [3]. Febuxostat is either comparable to or more effective than allopurinol in terms of urate‐lowering efficacy [8, 9], and is safer in patients with severe chronic kidney disease (CKD) [10]. In patients with CKD stage 3a and asymptomatic hyperuricemia, febuxostat provides better renal protection than benzbromarone [10]. Although febuxostat has received a boxed warning from the U.S. Food and Drug Administration for increased risk of mortality in patients with cardiovascular comorbidities following the CARES trial, a recent global meta‐analysis did not show significant differences in cardiovascular outcomes between febuxostat (40 or 80 mg per day) and allopurinol (200–300 mg per day) [8]. Furthermore, Asians have a higher risk of allergic reaction to allopurinol due to the prevalence of HLA‐B*5801, which may affect the risk–benefit ratio in the Chinese population.

Allopurinol is recommended by guidelines in many countries as a first‐line treatment in patients with asymptomatic hyperuricemia. Compared to allopurinol, benzbromarone may reduce the risk of dialysis by approximately 50% in patients with asymptomatic hyperuricemia and CKD. Benzbromarone has urate‐lowering effects similar to those of febuxostat [11], and is particularly effective in patients with poor renal urate excretion [11]. Therefore, both allopurinol and benzbromarone are recommended as first‐line treatment.

Currently, there is insufficient evidence to support discontinuing medication in patients with asymptomatic hyperuricemia. A small subset of patients may be able to maintain SU levels below 360 μmol/L through diet, exercise, and management of metabolic syndrome. Meta‐analyses suggest that excessively low SU levels are associated with an increased risk of neurodegenerative diseases. Therefore, we suggest that patients on low‐dose urate‐lowering agents who maintain SU levels ≤ 360 μmol/L for 3 months or achieve SU levels below 240 μmol/L on at least two separate occasions may consider discontinuing ULT, provided they maintain a healthy lifestyle and regularly monitor their SU levels.

3.2. Urate‐Lowering Therapy Guided by Renal Urate Excretion

The classification of hyperuricemia, based on 24‐h urinary urate excretion (UUE) and fractional excretion of renal urate (FE_UA ), is recommended to guide ULT selection; for renal underexcretion, benzbromarone is the preferred agent, while for combined hyperuricemia (UUE between 600 and 700 mg), low‐dose febuxostat and an add‐on low‐dose benzbromarone if necessary are suggested.

The 2019 Guideline clarified that hyperuricemia classification should be determined based on a combination of baseline UUE and FE_UA [3]. The 2016 European Alliance of Associations for Rheumatology (EULAR) guideline recommended assessing renal urate excretion prior to initiating ULT in gout patients with early onset or a family history of early onset to guide medication selection [12].

A randomized controlled trial (RCT) conducted in Chinese gout patients with renal urate underexcretion found that benzbromarone (25 mg/day) was more effective than febuxostat (20 mg/day) in achieving SU target levels, with fewer occurrences of abnormal liver function [11]. A cohort study conducted over 3 months showed that benzbromarone (25 mg/day) led to a higher SU target achievement rate in patients with renal underexcretion compared to unclassified patients [13]. However, it should be avoided in patients with UUE > 700 mg on a low‐purine diet or > 800 mg on a regular diet, which indicate a dominant renal urate overload due to the possibility of renal damage [14]. A RCT study demonstrated that adding benzbromarone (25 mg/day) to febuxostat (20 mg/day) achieved superior urate‐lowering efficacy compared to febuxostat monotherapy in gout with combined hyperuricemia over three months [15].

3.3. Anti‐Inflammatory Therapy With Glucocorticoids for Recurrent Gout

Glucocorticoids initiated for recurrent gout flare are suggested to be tapered down slowly, generally within 1 month; Colchicine is recommended to prevent flares during glucocorticoid tapering; IL‐1 inhibitors are suggested for patients unresponsive to conventional therapies.

Systemic or intra‐articular glucocorticoids have been proved and suggested by previous guidelines for short‐term use in gout flares [5, 16, 17, 18]. For patients with recurrent gout (≥ 2 episodes per year), particularly those experiencing flares within 3 months after the last episode, or those not receiving prophylactic treatment during ULT, the tapering period may be extended to 14 or even 21 days, accompanying a low dose of colchicine. However, the total course of glucocorticoids therapy should adhere to the “Guidelines for Clinical Application of Glucocorticoid Drugs (2023 Edition)”, which generally limits short‐term use to 1 month.

The 2020 American College of Rheumatology (ACR) guidelines for gout management conditionally recommend IL‐1 inhibitors for patients who are unresponsive or intolerant to conventional anti‐inflammatory therapy [2]. Anakinra was shown to be not superior to a single dose of triamcinolone (40 mg injection) when administered at 100 or 200 mg/day for 5 days. Rilonacept showed comparable efficacy to indomethacin when administered as a 320 mg subcutaneous injection. Canakinumab significantly alleviated pain and inflammation and reduced the risk of flares in patients with acute gouty arthritis with a single 150 mg dose. Recently, an express letter reported that firsekibart, a fully humanized IL‐1β inhibitor administered as a single 200 mg subcutaneous injection, compared with compound betamethasone, demonstrated non‐inferior pain relief for acute gout attack and superior efficacy in delaying new flares within 6 months among Chinese patients [19]. Current evidence suggests that IL‐1 inhibitors are effective and safe for patients with gout flares who are unsuitable for standard therapies [20].

3.4. Management for Chronic Gouty Arthritis

For chronic gouty arthritis, ULT should aim to maintain SU levels between 180 and 300 μmol/L; flare prophylaxis is suggested to continue for at least 3 months after achieving target SU levels if there is no evidence of tophi; if tophi are present, prophylaxis is suggested to continue for at least 6 months after achieving target SU levels and the dissolution of tophi.

The primary goal in managing chronic gout is to maintain SU at lower levels to promote the dissolution of crystals and, in some cases, tophi. The 2012 ACR guidelines for gout management recommend maintaining SU level < 6 mg/dL for all gout patients, and < 5 mg/dL for those with tophi [21]. These targets were reaffirmed by the 2023 consensus recommendations of the Hong Kong Society of Rheumatology [5].

Guidelines also recommend low‐dose colchicine, NSAIDs, or low‐dose corticosteroids for gout flare prophylaxis for at least 3 months (for those without tophi) or at least 6 months (for those with tophi), with the duration potentially extended based on the dissolution status of tophi [22, 23]. In chronic gout, maintaining a constant, safe level of SU is crucial to prevent recurrent crystal formation and inflammation. Therefore, the EP reached consensus that prophylaxis treatment should not be discontinued until the SU target is stable for 3–6 months, depending on the presence of tophi.

IL‐1 inhibitors are a newer class of drugs for the treatment of acute gout. Some studies have explored the use of IL‐1 inhibitors as prophylactic agents, showing promising results; however, infection must be ruled out before administration, particularly in chronic gouty arthritis.

3.5. Auxiliary Therapy: Urine Alkalization

Urine alkalization is suggested for patients with hyperuricemia and gout, particularly those with a morning urine pH < 6.0 and taking uricosuric agents; citrate preparations are preferred; sodium bicarbonate is an alternative for patients who cannot tolerate citrate or have renal impairment; the dosage of alkalization agents should be adjusted to maintain morning urine pH levels between 6.2 and 6.9.

Excessively acidic urine is a key factor in the formation of uric acid stones. Urine alkalization can dissolve existing stones and prevent the formation of new ones [24]. A cross‐sectional study found that those with a urine pH ≤ 5.0 were at higher risk of renal damage [25]. A study has shown that allopurinol combined with citrate preparations significantly increased urine pH and FE_UA, while effectively reducing SU levels. Therefore, urine alkalization is recommended for hyperuricemia and gout patients, especially those on uricosuric agents, when the morning urine pH is < 6.0.

Citrate preparations have been found to be of comparable efficacy on urine alkalization but more effective in reducing gout flares, hematuria, urine albumin‐to‐creatinine ratio (UACR), and kidney stones and in improving the serum lipid profile [6, 26, 27]. Prolonged sodium bicarbonate use may increase sodium load, which heightens the risk of hypertension and promotes urinary calcium excretion, potentially increasing the likelihood of calcium stone formation. In summary, citrate preparations are considered the preferred agents for urine alkalization in patients with gout and asymptomatic hyperuricemia, while sodium bicarbonate should be used in cases of intolerance to citrate preparations or when renal impairment and metabolic acidosis are present.

The dosage of urine alkalization medications is primarily determined by urine pH levels. The goal is to maintain a morning urine pH between 6.2 and 6.9, which helps reduce the risk of uric acid kidney stones and promotes their dissolution. The recommended treatment duration is currently 3–6 months [6].

3.6. Auxiliary Therapy: Dietary Management

Dietary restrictions on high‐purine foods, high‐fructose products, and alcohol are recommended; while dietary fiber, tart cherry products, citric acid products, and skim milk are encouraged.

Excessive intake of purine‐rich food or ingredients that interfere with purine metabolism (such as fructose) or urate excretion (such as alcohol) may lead to hyperuricemia, and a low‐purine diet benefits the gout population in reducing sUA levels and cardiovascular–metabolic conditions, particularly in those with the urate overproduction phenotype [28]. Certain dietary patterns, such as the Mediterranean diet and DASH diet (the dietary pattern in Dietary Approaches to Stop Hypertension), are beneficial for patients with gout by improving hyperuricemia and metabolic syndrome. These diets are more beneficial compared to the western diet, which is characterized by high purine, fat, and calorie content [29, 30].

The consumption of carbohydrates, particularly fructose‐containing soft drinks, can exacerbate metabolic diseases and further elevate SU levels. Alcohol metabolism produces lactic acid, which reduces renal clearance of uric acid and decreases its excretion [31]. Certain alcoholic beverages, such as beer, contain high levels of purines, which can directly elevate SU levels. Additionally, alcohol increases the release of purines within the body, which are subsequently metabolized into uric acid, leading to elevated SU levels.

Dietary fiber helps support blood sugar control, improves insulin resistance, and promotes uric acid excretion [32]. Tart cherry preparations and citric acid products can alkalize urine, effectively reduce the frequency of gout flares, and lower SU levels [6, 33]. Population studies have also indicated that, compared to other protein sources, milk does not elevate SU levels [34].

3.7. Gout Management in Women of Reproductive Period

Lifestyle interventions should be prioritized. Benzbromarone and allopurinol are contraindicated during pregnancy, while febuxostat can be used cautiously. Allopurinol can be used during lactation. Low‐dose glucocorticoids, colchicine, and nonsteroidal anti‐inflammatory drugs (NSAIDs) are acceptable for managing gout flares.

Hyperuricemia during pregnancy is associated with adverse outcomes. Due to the lack of established diagnostic criteria for hyperuricemia during pregnancy and lactation, unclear initiation of treatment and targets, and insufficient clinical evidence for urate‐lowering medication for pregnant or lactating women, SU levels should primarily be managed through appropriate dietary and lifestyle modifications to ensure the safety of the fetus and nursing infants.

A systemic review suggests that allopurinol use during pregnancy may have teratogenic effects, especially during the first trimester [35]. Most guidelines recommend against the use of benzbromarone and allopurinol in pregnant women. Febuxostat may be considered only when the benefits outweigh the potential risks to the fetus. A case report showed that oxypurinol, the active metabolite of allopurinol, was detectable with low concentration in breast milk of a lactating woman taking 300 mg/day of allopurinol, and relatively low levels in the infant's plasma 2 h after breastfeeding, without adverse events after 6 weeks' exposure [36]. The American Academy of Pediatrics considers allopurinol compatible with breastfeeding.

During gout flares, low‐dose glucocorticoids, colchicine, and NSAIDs are generally considered safe and effective.

Overall, medication use during pregnancy and lactation should be carefully evaluated, weighing the risks and benefits, with consideration for the potential effects on both mother and infant.

3.8. Gout Management in Men of Reproductive Period

For men planning conception, discontinuation of allopurinol and febuxostat is recommended for at least 3 months in those with suspected infertility during treatment. Benzbromarone is recommended if necessary. Low‐dose glucocorticoids, colchicine, and NSAIDs are suggested for managing gout during this period.

Recent studies have indicated that hyperuricemia negatively affects sex hormones, semen quality, and contributes to erectile dysfunction (ED), while the impact of urate‐lowering drugs on male fertility and pregnancy outcomes remains unclear. One study reported temporary infertility in a patient treated with allopurinol, with sperm penetration test scores returning to normal after discontinuation [35]. A cohort study found that febuxostat may pose a higher risk of ED compared to allopurinol in male gout patients [37]. A prospective cohort study concerning the effects of allopurinol, febuxostat, and benzbromarone on sperm quality and sex hormones found that benzbromarone increased sperm concentration, while febuxostat exposure decreased sperm motility at three months [38]. However, the decision of ULT discontinuance should be based on a balanced risk/benefit evaluation. The 2016 EULAR recommendations on antirheumatic drugs during pregnancy and lactation, as well as the 2020 ACR guidelines on reproductive health management for patients with rheumatic and musculoskeletal diseases, suggest that men can use low‐dose NSAIDs, colchicine, and tumor necrosis factor inhibitors during the conception period [39].

3.9. Diagnosis of Mormouricemic Gout

The presence of MSU crystals in synovial fluid is recommended as the gold standard for diagnosing gout in patients with normouricemia. For those who cannot undergo joint aspiration or have negative results, alternative diagnostic tools such as ultrasound, dual‐energy CT (DECT), and X‐ray are recommended to detect MSU crystal deposits. Repeated SU assessment 2 weeks after a joint episode is recommended to obtain the authentic SU level to follow the 2015 ACR/EULAR diagnostic criteria.

Although elevated SU is a primary driver for MSU crystal formation and serves as an independent risk factor for gout flares, not all patients experience high SU levels during flare episodes. During gout flares, SU levels tend to decrease temporarily [40]. Therefore, for patients highly suspected of having gout, if their SU levels are normal during joint episodes, or do not meet the diagnostic criterion, it is recommended to recheck the SU level at least 2 weeks after the episode resolve [41].

In any cases, the presence of MSU crystals in synovial fluid or tophi remains the gold standard for diagnosis, as recommended in both the 1977 American Rheumatism Association criteria and the 2015 ACR/EULAR classification criteria [42]. For patients who cannot undergo joint aspiration or present negative results, newly developed technologies like DECT and ultrasonography are alternative diagnostic tools for patients without a history of hyperuricemia [43].

3.10. Assessment of Gout Flare Risk

Imaging techniques such as ultrasound and DECT, along with biomarkers like baseline SU, are suggested to be used to assess flare risk in patients with gout or asymptomatic hyperuricemia.

Gout flares not only cause severe pain, but they have also been recently linked to significant cardiovascular and cerebrovascular complications. Predicting and preventing flares in patients with intercritical gout or asymptomatic hyperuricemia is important for both healthcare providers and patients. Studies have demonstrated that the presence of MSU crystal deposition, confirmed via ultrasound and/or DECT, is a risk factor for flares within 1–2 years [44, 45]. These imaging modalities can also forecast the frequency of flares in joints with MSU crystal deposition following the initiation of ULT [46]. A systematic review revealed a positive correlation between the volume of urate crystal deposits detected by DECT and the risk of future flares [45].

In recent years, biomarkers have been increasingly used to support both the diagnosis and prediction of gout flares. Emerging biomarkers and multi‐omics predictive models have shown potential in forecasting gout flares and frequent attacks [7, 47, 48]. A prospective cohort study involving 193 gout patients identified serum cancer antigen (CA) 72‐4 as an independent risk factor for gout flares [47]. A cohort study investigating patients with infrequent or frequent gout, using mass spectrometry‐based untargeted metabolomics, established a predictive model for frequent gout attacks [7]. Another cohort study also identified seven characteristic metabolic markers that distinguish gout from hyperuricemia using mass spectrometry [48]. However, these findings require further validation through multicenter and prospective studies.