Standardized treatment of gout
Abstract: The standardized treatment of gout is very important. First, a comprehensive assessment of the patient’s condition is needed, including blood uric acid and 24-hour uric acid levels, the presence of gout stones, frequency of gout attacks, whether the kidneys are involved, the presence of comorbidities and uric acid metabolism, etc. The appropriate treatment plan and medication should be selected according to the condition. In case of gout attack, anti-inflammatory and analgesic treatment is the main focus, and early and adequate use of drugs is more important than the choice of drugs. In the process of uric acid reduction treatment, non-pharmacological treatment is emphasized as the foundation, maintaining uric acid consistently at the standard is the key, and preventing gout attacks can improve treatment compliance.
In recent years, with the improvement of living standards and lifestyle changes, the incidence of gout, a historical disease of affluence, has been increasing, and its incidence in China rose from 0.33% in 1998 to 1.34% in 2003, and has become a common disease in rheumatology outpatient clinics. At the same time, the medical profession has conducted a lot of research on gout in recent years, and has made great progress in many aspects such as the treatment strategy of gout, the development of new drugs and the usage of traditional drugs, etc. This paper seeks to achieve the purpose of standardizing gout treatment by analyzing the key issues in gout treatment.
I. Correct assessment of the patient’s condition
The treatment strategy of gout has changed from simple uric acid lowering and pain relieving treatment to comprehensive management of gout disease. The treatment strategy differs with different conditions, so the first step is to evaluate the patient’s condition. The patient’s overall situation should be understood, including the patient’s blood uric acid level, whether the gout is recurrent, whether there are gout stones, whether there is joint destruction, whether there is kidney involvement, whether there are comorbidities, whether there are secondary factors, and whether the uric acid metabolism is of the increased production or decreased excretion type. The correct interpretation of blood uric acid level should first clarify the clinical significance of the patient’s blood uric acid level (see Table 1).
Second, the correct treatment strategy
1.Non-pharmacological treatment is the basis of gout treatment
Non-pharmacological treatment is as important as drug treatment in gout treatment, including patient education, diet control, weight loss, smoking cessation and control of comorbidities. Diet control is crucial in uric acid lowering treatment, and strict diet control can reduce blood uric acid level by 1mg/dl.
2.Preventive treatment of gout
Prevention of gout attack is crucial in uric acid-lowering drug therapy. To prevent gout attack, firstly, it should be achieved to lower uric acid smoothly, all uric acid-lowering drugs should start from small dose and gradually increase the dose, in order to lower blood uric acid smoothly; secondly, preventive anti-inflammatory and analgesic drugs such as small dose colchicine or NSAIDS should be used in combination at the beginning of uric acid-lowering treatment. The duration of prophylactic drug application differs from country to country, with our guidelines suggesting a duration of at least 1 month and EULAR guidelines suggesting 6-12 months, while the ACR guidelines suggest that prophylactic treatment should be continued for those with gout symptoms (within 3 months of acute gout, gout stones, chronic gouty arthritis), and for those without the above-mentioned gout symptoms, prophylactic treatment should be given for at least 6 months. For those without the above-mentioned gout symptoms, preventive treatment should be given for at least 6 months. In clinical practice, the length of prophylactic treatment cannot be generalized, but should take into account the risk of recurrent gout attacks, the cost of prophylactic treatment, adverse effects and benefits.
3. Sustained achievement of uric acid standard
According to the latest guidelines, the goal of gout treatment is “cure”, but it is difficult to achieve this in clinical practice. The most critical reason why gout is difficult to be “cured” is that the reduction of uric acid is not in place, and even if it is, it is often difficult to maintain it. The key to the treatment of gout is to achieve a sustained blood uric acid standard, and long-term control of uric acid below <6mg/dl will not only dissolve existing urate crystals, but also prevent the formation of new crystals. The lower the blood uric acid level, the lower the recurrence rate of gout. The recurrence rate of gout in patients with blood uric acid <300μmol/L is less than 10%, while the recurrence rate in patients with blood uric acid >540μmol/L is as high as 80%. In addition, the rate of gout stone dissolution is the fastest when the blood uric acid level is kept below 240 μmol/L, and the gout stone can be completely dissolved in patients within 20 months on average. Therefore, maintaining the blood uric acid level for a long time is the key to the treatment of gout.
Third, the correct choice of drugs
1.Acute phase drug treatment
In the acute phase of gout, anti-inflammatory and analgesic treatment is the main treatment. For the choice of drugs in the acute attack period, the ACR guidelines recommend first-line drugs as NSAIDS, colchicine and glucocorticoids, and the Chinese guidelines recommend first-line drugs as NSAIDS and colchicine. The timing of drug use is now considered more important than the type of drug, and the earlier the better, preferably applied within 24 hours of the onset of the attack, and NSAIDS drugs should be applied in adequate doses. Colchicine is no longer recommended for traditional high-dose usage, but recommended for low-dose application, i.e., a loading dose of 1mg is given after an acute attack, 0,5mg is given again after 1h, and up to 0,5mg tid can be given after 12h. For refractory patients, anti-TNF-α inhibitors, tramadol, and cyanoplasm can be considered.
2.Uric acid-lowering drug treatment
About the timing of application of uric acid-lowering drugs should be noted: for the first acute gout attack patients do not temporarily add uric acid-lowering drugs, once added, another attack without stopping the drug, which is consistent with the views of national guidelines. The traditional view is that during acute attacks, analgesic and anti-inflammatory drugs should be the mainstay, and no uric acid-lowering drugs should be added temporarily. In contrast, the 2012 ACR guidelines proposed for the first time that uric acid-lowering medication can be started during acute attacks of gout with adequate anti-inflammatory and analgesic conditions. An RCT study confirmed that the addition of allopurinol therapy to indomethacin therapy during the acute phase of gout does not affect pain relief [8], but there are no RCT studies with larger samples to further confirm this view. For chronic gout without intermittent periods, anti-inflammatory analgesic therapy should be added to uric acid-lowering medication.
Drug selection for uric acid-lowering therapy: 24-hour uric acid should be measured before the start of uric acid-lowering drug therapy to determine the patient’s uric acid metabolism and guide drug selection. For the poor uric acid excretion type and most early and middle stages of gout, uric acid excretion should be promoted; for the excessive uric acid synthesis type and most middle and late stages of gout, uric acid synthesis should be inhibited.
Among the available uric acid excretory drugs, benzbromarone should be preferred for the following reasons.
(1) The efficacy of benzbromarone is significantly better than that of propofol, with 92% and 65% of the target rate, respectively; and its efficacy is also better than that of allopurinol, with 52% and 26% of the target rate, respectively.
(2) Low side effects: low requirement for renal function, Ccr>25ml/min, while propofol requires Ccr>80ml/min.
(3) Few drug interactions: only hydantoin and benzosulfanilone weaken the uric acid excretion of benzbromarone. RDEA-594, a second-generation uric acid excretory agent, is not yet available, and has a similar mode of action to benzbromarone, with the outstanding feature of no hepatotoxicity.
Allopurinol is a commonly used drug to inhibit uric acid synthesis. It should be started in small doses and increased slowly, with the starting dose not exceeding 100 mg/d. Patients with moderate to severe CKD should start with a smaller dose (50 mg/d), and the dose can be gradually increased to more than 300 mg/d in the absence of allergic reactions. The dose should be reduced in patients with renal insufficiency and is contraindicated in Ccr<15ml/min. Allopurinol should be used with concern for adverse reactions. About 5% of patients may develop severe hypersensitivity syndrome (stevens-Johnson syndrome, toxic epidermolysis bullosa, etc.), with a mortality rate of 20%-25%. Risk factors for hypersensitivity reactions include renal insufficiency, thiazide diuretics, and HLA-B*5801 positivity. HLA-B*5801 gene positivity is 6-12% in Asians, so the 2012 ACR recommends that HLA-B*5801 should be tested rapidly before allopurinol is used in Asians, and those who are positive should be prohibited, and the gene should be tested before the drug is administered when available (implemented in Taiwan in 2008).
Another xanthine oxidase inhibitor, febuxostat, was approved for marketing by the FDA in 2009 and introduced in China in 2013, and has been classified as a first-line uric acid-lowering drug by EULAR and ACR. Compared with allopurinol, febuxostat has obvious advantages [10]: it has no purine-like backbone, and lethal allergy syndrome rarely occurs, especially for allopurinol allergic patients; it inhibits both oxidative and reductive xanthine oxidase, and has a stronger inhibitory effect on uric acid production; it does not require dose adjustment for mild to moderate hepatic or renal impairment, and is safer for renal insufficiency. It is effective and safe for patients who are not suitable for allopurinol treatment and is well tolerated. However, it is not suitable for patients with severe liver damage (hepatic metabolism), coronary artery disease and heart failure.
For refractory gout, a combination of two uric acid-lowering drugs may be considered, usually a pro-uric acid excretory drug plus an inhibitor of uric acid production, but not a combination of similar drugs.
For patients with comorbidities, the combination of uric acid excreting drugs can be used to kill two birds with one stone. The antihypertensive drug coxsartan can increase uric acid excretion rate by 30% by inhibiting uric acid reabsorption in the proximal tubule; fenofibrate can promote uric acid excretion and reduce blood uric acid by 15-30% while lowering triglycerides; for patients with combined hyperlipidemia and coronary artery disease, atorvastatin can be applied, which not only lowers cholesterol but also lowers uric acid by 6,4-8,2%.
In addition, a new drug to promote the decomposition of uric acid, Prescriptive, has been marketed abroad. By breaking down uric acid in the body, it can rapidly deplete the uric acid pool and lower the blood uric acid level. Its outstanding advantage is that the gout stone disappears quickly. However, the incidence of infusion reaction in clinical application is high about 8-11%. In addition, the frequency of acute gout attacks induced by the use of the drug is also an important problem limiting its application. Therefore, Precahi is currently used only in adult patients with refractory gout for whom conventional uric acid-lowering therapy has not been effective.
To sum up, maintaining a sustained blood uric acid level is the core of gout treatment, and is also the goal of treatment and guarantee of recovery. The key to achieving the standard is to pay attention to diet control during the treatment process, to select appropriate uric acid-lowering drugs on this basis, and to provide timely anti-inflammatory and analgesic treatment during acute attacks. In addition, lifestyle guidance and treatment of comorbidities should be emphasized.