With the continuous improvement of living standard and change of diet structure, gout has changed from “king’s disease” to “king of the diseases”. diseases.) In October 2012, the American college of rheumatology (ACR) officially released the “2012 ACR Gout Treatment Guidelines” (hereinafter referred to as the “Guidelines”). The “Guidelines”). Compared with the previous guidelines issued by other countries and organizations, this guideline contains many new contents that are worth studying and thinking about. In this article, we introduce the 2012 ACR Gout Treatment Guidelines and review their contents.
The “Guidelines” are divided into two parts. The first part focuses on “uric acid-lowering therapy” and “treatment of chronic gouty stone gout”; the second part focuses on “analgesic therapy”, “anti-inflammatory therapy” and “gout The second part deals with “analgesic therapy,” “anti-inflammatory therapy,” and “anti-inflammatory drug prophylaxis for gouty arthritis attacks.
Epidemiology
The current prevalence of gout among adults in the United States is 3.9%, with approximately 8.3 million people affected by gout nationwide. The increase in the number of patients with gout is mainly related to the comorbidities that promote hyperuricemia: hypertension, obesity, metabolic syndrome, type II diabetes, increased prevalence of chronic renal insufficiency (CKD), and changes in dietary habits and increased use of thiazide diuretics and tab diuretics.
Commentary: The rising economy of developing countries such as China, the improving standard of living and changing dietary structure are the main reasons for the increasing incidence of gout/hyperuricemia in recent years. In developed western countries such as the United States, where the economy has reached a relatively stable stage and the diet is basically in a “stable” state, co-morbidities that cause hyperuricemia and pharmacological factors may be the main factors contributing to the increasing prevalence of gout.
Patient education and management of comorbidities
Patient education, including dietary guidance, promoting a good lifestyle, and informing patients of the goals of treatment, as well as aggressive treatment of comorbidities that can lead to hyperuricemia, is a core component of treatment.
Commentary: Active and effective patient education is an important part of the treatment of chronic diseases. Data from epidemiological surveys at the European League Against Rheumatism (EULAR) conference show that gout patients have widespread misconceptions about the disease, lack knowledge about standardized uric acid-lowering therapy, and have poor medication adherence. Family physicians and non-rheumatologists also lack the concept of standardized treatment. Therefore, the guideline emphasizes the importance of “education” and suggests that active control of co-morbidities that can lead to hyperuricemia is an important part of gout prevention and treatment, which deserves attention.
Uric acid-lowering therapy
The xanthine oxidase inhibitors allopurinol and febuxostat are the first choice of uric acid-lowering drugs. Uric acid-lowering therapy should result in effective and sustained improvement in signs and symptoms, and uric acid levels should be reduced to at least <6 mg/dl and generally <5 mg/dl, or the goal of uric acid-lowering for all patients with gout is blood uric acid <6 mg/dl, but for patients with gout stones, it should be reduced to less than 5 mg/dl.
The starting dose of allopurinol should not exceed 100mg/d, and patients with moderate or severe chronic renal insufficiency should start with a smaller dose (50mg/d) and gradually increase the dose to find a suitable maintenance dose. The maintenance dose can exceed 300mg/d, even in patients with CKD. For patients taking doses greater than 300mg/d, scratching, rash and increased liver enzymes should be noted, and severe drug rash can be detected early.
For specific populations, such as those of Korean descent with concurrent grade 3 or higher CKD; all Chinese Han Chinese, and Thai descent, who are at increased risk for severe allopathic drug rash associated with allopurinol because of high HLA-B*5801 positivity, rapid HLA-B*5801 PCR testing should be performed prior to allopurinol administration.
If a single xanthine oxidase inhibitor (XOI) does not achieve the therapeutic goal (attainment) after increasing to an appropriate dose, a combination of a drug that promotes uric acid excretion (uricosuric) may be used. These drugs include propofol, fenofibrate (off-label use), and cloxacin (off-label use) available in the US market, but exclude benzosulfanilone and benzbromarone.
During acute attacks of gout, uric acid-lowering therapy may be initiated if anti-inflammatory drugs are already being used.
Commentary: The concept of standard treatment is emphasized in the guideline, and the target value of uric acid-lowering treatment is clearly proposed, which is very important for the evaluation of the treatment effect and ensuring the long-term stability of patients’ condition. For patients with gout stones, more stringent treatment targets are set to facilitate the absorption of gout stones.
In the choice of uric acid-lowering drugs, the xanthine oxidase inhibitors allopurinol and febuxostat are preferred, while benzbromarone, which is widely used in China, is not recommended. The main reason for this is that benzbromarone was once found to cause liver failure in the United States, so it was banned by the FDA and is no longer available in the U.S. market. Another reason is that the rate of HLA-B*5801 positivity in the US population is significantly lower than in some Asian populations, and severe allopurinol-related drug rash, which is prone to occur in Asian populations, is uncommon, thus qualifying allopurinol as the drug of choice. Febuxostat is a new xanthine oxidase inhibitor that has been marketed in recent years, and its uric acid-lowering effect is comparable to or slightly better than that of allopurinol, and studies have shown that it causes significantly less drug rash than allopurinol, so it has broad market prospects. However, the drug is not yet available in China, and even in the United States and Europe, it is still very expensive. It was chosen as the preferred uric acid-lowering drug along with allopurinol, apparently only for clinical efficacy reasons, without taking into account pharmacoeconomic factors. This is also frankly stated in the “Guidelines”. In China, due to the relatively high incidence of severe drug rash associated with allopurinol and the relatively low incidence of severe hepatic impairment associated with benzbromarone, as well as the fact that febuxostat is not currently available in China, differences from the ACR guidelines should be considered in the selection of uric acid-lowering drugs.
It is well established that severe drug rash associated with allopurinol is strongly associated with HLA-B*5801. In some Asian populations, it has been a medication concern for Asian gout patients because of the high rate of positivity for this gene. As early as 2008, the local administration in Taiwan has issued a directive that this gene must be tested before taking allopurinol. However, the test is not widely available in Asian patients. This time, the “guideline” specifically emphasized the importance of HLA-B*5801 testing. The author’s research group successfully developed a method for rapid PCR testing of this gene a year ago and filed a patent for the invention, which is now in the process of being converted into a product.
The use of allopurinol should be started at a small dose for the following reasons: starting at a small dose reduces the possibility of triggering a gout attack; severe drug rash associated with allopurinol is related to the dose of the drug. 2010 edition of the Chinese Gout Guidelines also suggests starting at a dose of 100 mg/d, but in practice, this point is often overlooked, especially in primary care and among non-specialists.
For patients who cannot “reach the target” even after using sufficient xanthine oxidase inhibitors, drugs that promote uric acid excretion can be combined, and this idea has been accepted earlier in China. However, it is worth noting which drugs to combine and when to start the combination. What is “sufficient amount”? The author believes that it should be the maximum permissible dose contained in the drug’s instruction, but the possible adverse effects at the maximum dose should be fully considered, and more caution should be exercised in patients with renal insufficiency.
Fenofibrate, coxsartan and other drugs were not originally used for uric acid-lowering treatment, but in the use of these drugs are found to be conducive to promoting the secretion of uric acid in the kidneys, so patients with hyperuricemia should give priority to these drugs when choosing lipid-lowering drugs and antihypertensive drugs. However, in patients with gout, these drugs are not recommended for uric acid-lowering therapy alone, but can be combined with xanthine oxidase inhibitors to improve the effect of uric acid-lowering therapy.
Most international gout treatment guidelines, including Chinese guidelines, suggest that uric acid-lowering therapy should be started only after the acute attack has subsided for at least 2 weeks, on the grounds that the use of uric acid-lowering therapy during an acute gout attack may aggravate the symptoms of gout. “The guidelines suggest for the first time that uric acid-lowering therapy is not contraindicated under the “protection” of effective anti-inflammatory drugs. This new view deserves to be confirmed in future clinical practice.
Uric acid excretory drugs
If monotherapy is used, probenecid is the drug of choice; fenofibrate and cloxacin have therapeutic uric acid-lowering effects; uric acid excretory drugs are contraindicated as monotherapy in patients with a history of urinary tract stones; uric acid levels should be measured before the use of uric acid excretory drugs and followed up during treatment; adequate water intake, alkalinization of urine, and testing of urine pH should be ensured during treatment.
Commentary: The guideline does not give the first choice to uric acid-promoting drugs, which is in line with the idea of starting at the source. However, some patients who do not respond to or tolerate xanthine oxidase inhibitors may still have the opportunity to use uric acid excretory drugs. For the reasons mentioned above, the use of benzbromarone is not recommended. The importance of alkalinizing the urine in the use of pro-uric acid excretory drugs is emphasized because more uric acid is excreted from the kidneys during drug use, and alkalinizing uric acid increases the amount of uric acid dissolved and may prevent deposition of urate crystals in the kidneys or the formation of stones. Measurement of uric acid plays an important role in the selection of this class of drugs and in evaluating the effectiveness of treatment. In normal people, uric acid is generally <600 mg/d. Pro-uric acid excretory drugs are suitable for those with low uric acid levels, but when uric acid is significantly increased, treatment with such drugs is not recommended.
Uric acid enzymes and combined medications
In patients with severe gout who are resistant or intolerant to conventional uric acid-lowering therapy, treatment with uricase (Prescriptive, Pegloticase) may be used, but there is a lack of consensus on how long the dosing period should be. In patients with gout, those taking small doses of aspirin to prevent cardiovascular disease hazards are not required to stop taking it.
Commentary: Uric acidase can directly break down excess uric acid in the body and is a new option for gout uric acid-lowering treatment. The drug is a biological agent, expensive, and its possible allergy and drug resistance are common features of biological agents, so it is recommended as a “second-line drug”. Small doses of aspirin can inhibit uric acid excretion by the renal tubules, which is thought to be an important cause of hyperuricemia. Previously, for gout patients taking aspirin in combination, doctors often recommended that patients take other anticoagulants as an alternative. “The guidelines suggest that for patients with gout, the negative effects of aspirin are negligible, so there is no need to discontinue or change medication.
Uric acid-lowering therapy in renal insufficiency
In patients with grade 2-5 CKD or end-stage renal disease, if they have had a gout attack and currently have hyperuricemia, they should be treated with uric acid-lowering therapy; for the assessment of renal insufficiency, Ccr is more important than blood creatinine; since there is no data on the safety of febuxostat in patients with grade 4 or higher CKD, propofol can be used as a first-line drug; for Ccr<50ml/min, propofol alone is not recommended as a first-line drug.
Commentary: Renal insufficiency on the one hand can be a complication of long-term gout, and in addition renal insufficiency caused by various renal diseases or systemic diseases can also lead to the occurrence of secondary gout. The treatment of uric acid reduction in patients with renal insufficiency has always been a difficult problem. The “guidelines” are very important for the prompting of medication for patients with renal insufficiency.
Blood uric acid monitoring
Blood uric acid monitoring is necessary for the treatment of gout. It is measured every 2-5 weeks during the adjustment of uric acid-lowering drugs. It should also be measured every 6 months after the standard has been reached (blood uric acid <6 mg/dl). The uric acid measurement is the basis for adjusting the dose of medication and also helps to determine the patient's compliance with the treatment medication.
Commentary: The importance of monitoring blood uric acid during the treatment of gout patients has been generally recognized. However, the time interval for monitoring is not clearly defined. “The guideline clearly puts forward the periodicity of blood uric acid monitoring, especially the testing every 2-5 weeks during the use of uric acid-lowering drugs, which is consistent with the recommended adjustment of drug dose every 2-5 weeks.
Non-pharmacological treatment
Non-pharmacological treatment includes weight loss in obese individuals, trying to return to a normal body mass index (BMI), promoting a healthy diet, appropriate exercise, quitting smoking, and ensuring adequate water intake. Dietary recommendations are shown in Table 1.
Table 1. dietary recommendations for gout patients
Note: Grade B and C refer to the level of evidence of evidence of evidence-based medicine
Commentary: The importance of non-pharmacological treatment of gout is well known. However, red wine has been considered appropriate for use in alcohol, and some studies have even suggested that red wine is beneficial for gout patients, but the Guidelines include all wines in the “less to eat (drink)” category. For dairy products, “low-fat” and “skim” were not emphasized in the past, but they are proposed in the “guidelines”, which should be due to the consideration of obesity and other co-morbidities. The “guidelines” do not recommend soy products and soy milk in the Oriental diet.
Management of Acute Gout
Within 24 hours after the onset of acute gout, medication should be given; during the acute attack, uric acid-lowering drugs already used can be continued; non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and colchicine are the first-line treatment for acute arthritic attacks.
Colchicine should be started within 36 hours of a gout attack. If a 1.2 mg/tablet formulation is used, start the loading dose at 1.2 mg and take 0.6 mg after 1 h. After 12 h, follow 0.6 mg, qd-bid; for a 1 mg/tablet formulation, start the loading dose at 1.0 mg and take 0.5 mg after 1 h, available up to 0.5 mg after 12 h,. tid.
The recommended dose of glucocorticoids is 0.5mg/kg of prednisone, with discontinuation for 5-10 days of continuous dosing. Alternatively, 0.5 mg/kg should be started for 2-5 days and tapered down and discontinued over 7-10 days.
In terms of NSAIDs, the choice is COX-2 inhibitors, etoricoxib is recommended, and in the case of celecoxib, a high dose should be used and the risk/benefit is uncertain; in severe and recalcitrant cases, glucocorticoids + colchicine or NSAIDs + colchicine can be used in combination.
Commentary: The first-line drugs recommended in the guideline are already widely accepted in clinical practice. “The guideline further clarifies how colchicine should be administered. For a long time, many gout guidelines (including the 2010 edition of the Chinese guidelines) have recommended an initial dose of 1.0 mg, followed by 0.5 mg every 1-2 hours, with a total dose of no more than 6 mg over 24 hours. “The emphasis on starting regular dosing 12 hours after the first two doses is based on the finding that the blood concentration of colchicine decreases significantly after 12 hours of dosing, and therefore regular dosing twice or three times a day should be started after 12 hours.
In terms of NSAIDs selection, etoricoxib has been approved by the FDA for the indication of acute gout treatment and therefore becomes the recommended specific COX-2 inhibitor.
It is worth emphasizing that in terms of combined medication, the combination of glucocorticoids and NSAIDs is not recommended, mainly because of the common GI side effects of these two drugs, and the combination will increase the possibility of peptic ulcers and bleeding, which should be avoided.
Preventive medication for gout
Oral colchicine and low-dose NSAIDs are the first-line drugs for the prevention of gout attacks. Colchicine 0.5 mg qd or bid is the first choice when starting uric acid-lowering medication, or low-dose naproxen 250 mg bid in combination with a proton pump inhibitor. If these drugs are ineffective, a low-dose glucocorticoid, prednisone Q10mg/d, may be used. For those with signs of gout activity, the medication should be continued for 6 months. Signs of gout activity include: (i) gout stones found on physical examination; (ii) recent acute gout attack; (iii) chronic gouty arthritis and/or blood uric acid level not reaching the standard. Or for patients on uric acid-lowering therapy, continued medication until 3 months (for those without gout stones) or 6 months (for those with gout stones) after the blood uric acid standard has been reached.
Commentary: Prevention of gout includes prevention of reoccurrence after an acute attack and prevention of “secondary gout” induced by taking uric acid-lowering drugs in the past. Although some patients with gout may have normal blood uric acid levels during acute attacks or in isolated laboratory tests, they must have hyperuricemia during the course of the disease, and “there is no gout without uric acid! Therefore, uric acid-lowering therapy is indicated for most gout patients. Therefore, the prevention of gout attack is actually the prevention of gout re-attack during the course of uric acid-lowering therapy.
All of these preventive drugs have been used clinically in the past, but they are all significantly inadequate in terms of the course of treatment. The reason why glucocorticoids are included in the second-line preventive drugs is mainly because of the possible adverse effects of long-term use of glucocorticoids.
In this article, the 2012 “American College of Rheumatology Guidelines for the Treatment of Gout” are interpreted and reviewed. It should be noted that developed countries have strict procedures and regulations in the process of guideline development, which are more scientific and of greater reference value, and are worthy of our reference in the development of our own guidelines. In the ACR guidelines, it is specifically mentioned that the “guidelines” do not recommend treatment for simple hyperuricemia due to the lack of information from randomized controlled studies, which fully demonstrates the objectivity and rigor of the “guidelines” formulation process. Of course, due to the differences in ethnicity, economic level, and available drugs, the US guidelines may not be fully suitable for the Chinese situation, and their rationality and scientific validity will be tested in future clinical practice.