Combing through the "Gout Guidelines" at home and abroad in the past five years, answering the five major questions of uric acid reduction treatment

The prevalence of hyperuricemia in China is 13.

The guidelines related to gout issued in the past 5 years include the 2016 China Gout Diagnosis and Treatment Guidelines, the 2016 European Anti-Rheumatism Alliance (EULAR) Gout Management Recommendations, the 2017 Chinese Multidisciplinary Expert Consensus on the Diagnosis and Treatment of Hyperuricemia-related Diseases, the 2017 British Society of Rheumatology (BSR) Gout Management Guidelines, the 2019 Chinese Hyperuricemia and Gout Diagnosis and Treatment Guidelines, 2019 Gout and Hyperuricemia Primary Diagnosis and Treatment Guidelines and 2020 American Society of Rheumatology (ACR) Gout Management Guidelines, etc

These guidelines all emphasize the importance of uric acid-lowering drug therapy for the management of patients with gout, but the recommendations for specific issues related to uric acid-lowering drug therapy vary from one guide to another, and some have caused clinical confusion

Goals of uric acid-lowering drug therapy

In 2006, EULAR first proposed the target treatment of uric acid reduction for gout, that is, blood uric acid (sUA) reached the standard and should be maintained below the target value for a long time, in order to dissolve tophi, remove MSU crystals deposited in the joints, prevent new crystal deposits, and gout can no longer occur

Subsequent domestic and foreign guidelines have emphasized the targeted treatment of uric acid reduction, and most guidelines have set a specific target value of sUA<360 μmol/L, while patients with tophi, chronic arthropathy, or frequent onset of gout should < 300 μmol/L

The 2017 BSR gout management guidelines are more stringent, targeting uric acid-lowering therapy for all gout patients at sUA<300 μmol/L

The 2020 ACR guidelines suggest that, due to lack of evidence, lower sUA target values are not set to enhance uric acid-lowering drug therapy

However, this does not mean that the lower the sUA drops, the better

Uric acid within the human reference range has important physiological functions, especially antioxidant and neuroprotective effects, and low sUA may increase the risk of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, so multiple guidelines propose that sUA should not be less than 180 μmol/L
when treating uric acid.

 

Indications for uric acid-lowering drug therapy

In patients with gout with frequent onsets of gout, chronic gout arthritis, or tophi, guidelines agree that uric acid-lowering drugs should be treated
.

However, for patients with early gout who do not have chronic impairment, such as those who have their first onset or who have only one episode per year, the recommendations vary from guideline to guideline
.

The 2016 Chinese Guidelines for the Diagnosis and Treatment of Gout consider that there are no indications for uric acid-lowering drugs at this time, while the 2016 EULAR guidelines recommend that all patients with gout can consider uric acid-lowering drugs
.

The 2017-2019 China guidelines, the 2017 BSR guidelines, and the 2020 ACR guidelines all recommend that patients with the first episode of gout need to have an additional condition to be treated
with uric acid-lowering drugs.

The 2020 ACR guidelines also recommend that patients with infrequent attacks with < 2 episodes/year of infrequent attacks also be treated<b10> with uric acid-lowering drugs.

However, the guidelines differ in their provisions for conditions attached
.

Overall, foreign guidelines are more stringent, such as the 2017 BSR guidelines for renal impairment, history of urinary tract stones, combined use of diuretics, and gout
attacks at a young age.

The 2020 ACR guidelines are limited to sUA> 540 μmol/L, stage CKD3 and above, and the presence of urinary stones
.

In addition to the above situations, sUA >480 μmol/L, evidence of MSU deposition in the joint cavity, hypertension, glucose intolerance or diabetes, dyslipidemia, obesity, coronary heart disease, stroke and cardiac insufficiency, believe that gout can not only cause joint inflammation, but also adversely affect the cardiovascular system and kidneys, shorten life expectancy, so early intervention should be done
.

For asymptomatic hyperuricemia, China's guidelines are more positive, recommending that patients with sUA > 540 μmol/L start uric acid-lowering drug therapy, while the 2020 ACR guidelines conditionally oppose the start of uric acid-lowering drug therapy
in asymptomatic patients with hyperuricemia.

 

Timing of initiation of uric acid-lowering drug therapy

In patients with gout indicated for uric acid-lowering drugs, the ability to start using uric acid-lowering drugs during acute onset of gout is controversial
.

The BSR Gout Management Guidelines and several guidelines in China follow the traditional concept and recommend starting uric acid-lowering drug therapy
after the acute attack of gout has remissioned.

Both the 2012 and 2020 editions of the ACR Gout Management Guidelines recommend initiation of uric acid-lowering pharmacotherapy
in the acute phase.

The rationale for not treating uric acid-lowering drugs during acute episodes of gout is that sharp fluctuations in sUA may induce or exacerbate gout attacks
.

Randomized controlled studies found that the proportion of acute attacks of gout in the nonbutex 120 mg group was significantly higher than that in the nonbustad 80 mg group and allopurinol 300 mg group
.

The rationale for the ACR gout guidelines is that small randomized controlled studies have shown that patients with acute onset of gout have seen no difference in pain relief at 300 mg/d and placebo in the allopurinol 300 mg/day group and the number of gout attacks within 30 days, but the allopurinol group saw significantly lower than the placebo group
.

We believe that uric acid-lowering drug therapy is a long-term process, and for most patients with gout without chronic lesions, the start of uric acid-lowering drug therapy after 2 to 4 weeks is postponed has little
effect on its long-term efficacy and prognosis.

The main appeal of patients with acute onset gout is to control the acute attack as soon as possible, and then discuss uric acid-lowering drug treatment with patients in detail after control, which is more acceptable to
patients.

The real clinical pain of treatment is in patients with gout with severe chronic lesions, who may have almost no intermittent period
without joint swelling and pain.

At this point, consideration may be given to adding a small dose of uric acid-lowering drugs along with effective anti-inflammatory therapy
.

Lowering the initial dose of uric acid-lowering drugs can reduce the acute onset
of gout-inducing.

A randomized controlled study in Japan reported that patients with gout initiated by non-busteta from 10 mg/day, even without the addition of colchicine, had a higher frequency of acute onset than patients
who took nonbustaxate 40 mg/day and taking colchicine 0.
5 mg/day.

Choice of uric acid-lowering drugs

Currently available uric acid-lowering drugs worldwide include drugs that inhibit uric acid production (allopurinol, febuxita and topimastat), drugs that promote uric acid excretion (probenecid, benzbromarone, and resinald), and the uridase formulation pegologase
.

The only drugs listed in China are allopurinol, non-bustistat and benzbromomarone, these 3 drugs are the first-line uric acid-lowering drugs recommended by various guidelines in China, while the EULAR, BSR and ACR guidelines only recommend allopurinol as a first-line uric acid-lowering drug, of which the difference in adverse reactions in different countries is the main reason for
the difference between China's guidelines and foreign guidelines.

Allopurinol can produce fatal allopurinol hypersensitivity syndrome (AHS), and a positive human leukocyte antigen (HLA)-B*5801 is a high risk factor
for the development of AHS.

The proportion of Han Chinese people carrying this gene is 7.
4%, compared with only 0.
7% of
Caucasians.

From pharmacoeconomics, testing for HLA-B*5801 is better than not having
tested.

Therefore, patients with gout in China can be tested for HLA-B*5801 before using allopurinol, and other uric acid-lowering drugs can be selected if they are positive to avoid the risk
of AHS.

However, the reality is that at present, the level of medical institutions in various parts and levels in China varies greatly, and the genetic testing cannot be fully popularized
.

Febux was in the 2012 ACR gout guidelines as a first-line uric acid-lowering drug
juxtaposed with allopurinol.

However, recent findings that febuxtronate may increase cardiovascular adverse events
.

A multicenter randomized controlled study of cardiovascular safety (CAREs) using febux and allopurinol in patients with gout with cardiovascular disease, including a total of 6190 patients with gout with cardiovascular disease, found that the risk of cardiovascular-related death and all-cause death in the nonbutex group was increased
compared with the allopurinol group.

Because Caucasians do not have a high risk of developing AHS, EULAR, BSR, and ACR guidelines recommend allopurinol as a first-line agent and non-busteta as an alternative
.

Han People have a high risk of developing AHS, although there is a lack of data on cardiovascular adverse events in the Nonbusteta population in Our country, China's guidelines still recommend nonbuscidate as a first-line uric acid lowering drug
.

After the marketing of benzbromomarone in the 1970s, there were gradual reports of severe liver toxicity associated with it, and it was successively listed in some countries, and benzbrommarone is currently used
in Germany, Japan, Singapore and China.

In December 2014, China's Food and Drug Administration issued the "Warning of Liver Damage Risk Notice of Phenylbromaron", and from January 1, 2004 to December 31, 2013, 23 cases
of serious adverse drug reactions in the hepatobiliary system of Phenylbromarone were reported.

In 2004, Taiwan issued a warning of adverse drug reactions caused by liver damage caused by benzbromomarone, and caused a decrease in
the amount of prescriptions for benzbromomarone.

However, after the risk-benefit assessment of benzbromomarone organized by China's Food and Drug Administration, it is believed that the benefits of benzbromomarone in the treatment of gout in China are still greater than the risks, and it is recommended to start from low doses and conduct regular liver function tests to avoid combining
with other drugs with hepatotoxicity.

Therefore, China's guidelines still use benzbromomarone as a first-line drug
for uric acid-lowering therapy.

Course of uric acid-lowering drugs

Both domestic and foreign guidelines clearly emphasize that the goal of uric acid reduction in patients with gout is to maintain sUA below the target value for a long time
.

Recent studies have shown that the main influencing factor of sUA is genetic polymorphism, not diet
.

Thus, despite the low level of evidence in evidence-based medicine, guidelines in recent years have tended to explicitly recommend that uric acid-lowering drugs need to be taken for a long time in order to maintain sUA compliance
.

However, many people with gout are reluctant to take lifelong uric acid-lowering drugs
.

In fact, whether a patient with gout needs to rely on long-term use of uric acid-lowering drugs to maintain sUA below the target value depends more importantly on the patient's comprehensive uric acid-lowering measures
.

In addition to classic uric acid-lowering drugs, uric acid-lowering measures include non-pharmacological treatments such as dietary control, weight loss, and discontinuation of drugs that affect uric acid levels such as diuretics
.

Patients with comorbid gout may also have a tendency to choose drugs that also have a uric acid-lowering effect, such as losartan, atorvastatin, sodium-glucose synergistic transporter 2 inhibitors
.

The 2020 ACR guidelines take into account the adverse effects of fenofibrate and do not recommend the addition or switch to the drug
in patients with gout to lower uric acid.

After the deposited MSU crystals are completely dissolved, if the sUA can be achieved for a long time through the above measures, it is possible to avoid taking uric acid-lowering drugs
for a long time.

Perez-Ruiz et al.
reported that uric acid-lowering drugs in patients with gout were discontinued after 5 years of treatment, 13% of patients could maintain sUA at 360 to 420 μmol/L without gout attacks, and taking losartan, fenofact and discontinuing diuretics was associated
with sUA < 420 μmol/L.

In short, in recent years, domestic and foreign guidelines have emphasized the importance of long-term treatment with uric acid-lowering drugs, and continue to emphasize the importance of uric acid-lowering target treatment and long-term maintenance of sUA standards in patients with
gout.

In patients with gout without chronic lesions, different guidelines have different recommendations for the indication of uric acid-lowering drugs, and overall, the domestic guidelines are broader
.

There are still different views on whether uric acid-lowering drugs can be given during the acute phase of
a gout attack.

Based on the characteristics of patients in China, China's guidelines recommend allopurinol, nonbuscistat and benzbromomarone as first-line uric acid-lowering drugs, and physicians should be familiar with the adverse reactions and contraindications of these drugs
.

It is more important to study the guidelines developed by different countries and organizations, and it is more important to pay attention to the strength
of the evidence for the evidence-based medicine recommended by the guidelines.

In clinical practice, it is also necessary to combine the national conditions of different countries and the wishes of individual patients to formulate individual treatment plans
for patients.

Author: Dai Xian, Li Qianhua (Department of Rheumatology and Immunology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University)