Gout in which uric acid-lowering drugs have difficulty achieving the uric acid target. Clinically, patients with refractory gout are becoming more and more common, and clinicians tend to overlook the importance of “continuous compliance” treatment for uric acid.
I. Refractory gout should be taken seriously
With the improvement of people’s living standard, the prevalence of gout increases year by year, reaching 1.26%~1.59% and 0.3%~0.36% in men and women respectively in China, while refractory gout accounts for about 1% of the total number of gout patients, such as about 6.1 million cases of gout patients in the United States, there are about 50,000 cases of refractory patients. Patients with refractory gout have difficulty in achieving the standard blood uric acid level, recurrent arthritis attacks and poor efficacy of conventional analgesics, mostly accompanied by gout stone formation, joint deformity, renal insufficiency, hypertension, diabetes and coronary heart disease, which bring great pain to patients and affect their quality of life and life expectancy.
II. Proposal of “continuous standard” treatment
”The term “continuous standard” contains two meanings: “continuous” and “standard”. The longer the duration of the disease and the more gout stones in the body, the longer the duration of uric acid reduction may be. “For general gout, the ideal blood uric acid target value is <6mg/dl (360umol/L), while for refractory patients, it should be below 4mg/dl, which can bring This can provide the following benefits to the patient:
(1) Reduction in the frequency of acute arthritis attacks; Becke et al. showed that in 756 gout patients with blood uric acid >8mg/dl who were treated with febuxostat 120mg/d for 1 year to maintain the blood uric acid standard, the proportion of patients requiring treatment for acute gout attacks decreased from 23% to 6%.
(2) Rapid gout stone dissolution. The blood uric acid level was linearly and negatively correlated with the rate of uric acid stone dissolution, and the standard treatment contributed to the rapid dissolution of gout stones. The rates of gout stone dissolution in patients with blood uric acid in the range of 6.1-7 mg/dl, 5.1-6.0 mg/dl, 4.1-5.0 mg/dl and <4 mg/dl gout were (0.53 ± 0.59) mm/month, (0.77 ± 0.41) mm/month, (0.99 ± 0.50) mm/month and (1.52 ± 0.67) mm/month, respectively.
(3) It helps to slow down the progression of renal insufficiency. If high-dose allopurinol was used to treat gout patients with chronic renal insufficiency, the proportion of patients with renal deterioration requiring long-term dialysis decreased from 46.1% (control group) to 16% after the blood uric acid standard was consistently achieved.
(4) Improved prognosis of patients with combined heart failure. A retrospective study of 25,090 patients with gout found that continuous allopurinol for more than 30 d resulted in a significant reduction in heart failure readmission rates and all-cause mortality in patients with gout with heart failure (adjusted RR values of 0.69 and 0.74, respectively).
Strategies for “sustained compliance” of uric acid
For patients with refractory gout, non-pharmacological therapies should be emphasized throughout the treatment, such as strict control of high-purine diet, soft drinks and fructose, abstaining from beer and liquor, drinking more water (the amount of water should exceed 2000 ml in 24 hours) and alkalinizing urine (maintaining urine pH at 6.2-6.8). In addition, there are a number of areas that need to be emphasized in drug therapy.
However, most studies have shown that long-term low to medium doses of allopurinol do not reduce the incidence of lethal allergic syndrome and have poor uric acid-lowering efficacy, although it is possible to start with low doses such as 50-100 mg/d. However, starting at low doses such as 50-100 mg/d and gradually increasing the dose may reduce the risk of fatal allergic syndrome up to a maximum of 800-900 mg/d.
At higher doses, there is a significant increase in efficacy without an increase in adverse effects. Similarly, other uric acid-lowering drugs such as benzbromarone can also be increased gradually from small doses on the basis of strict monitoring of adverse reactions, and the dose can eventually exceed the conventional dose in order to achieve the blood uric acid standard.
2, advocate the use of “a double (three) carved” drugs Many drugs in lowering blood pressure, lowering blood lipids and (or) lowering blood sugar at the same time can also reduce blood uric acid, and have “a double” or even “a triple” effect. The “double” or even “triple” effect. Clofentezan and fenofibrate can lower blood uric acid by 15%-30% by promoting uric acid excretion while lowering blood pressure and triglycerides respectively, and they also have the advantages of increasing urinary pH without increasing urinary crystals and having anti-inflammatory properties without inducing acute gout attacks, which are suitable for gout patients with combined hypertension and hypertriglyceridemia respectively.
Atorvastatin can lower blood cholesterol level and reduce blood uric acid by 6.4%-8.2% by inhibiting uric acid synthesis, which is suitable for gout patients with combined hypercholesterolemia. Arholofenate and Arholofenate can reduce blood uric acid by 15%~29% by promoting uric acid excretion in a dose-dependent manner while lowering sugar and triglycerides, which is suitable for gout patients with both diabetes and hyperlipidemia.
3, also to talk about the combination of drugs For patients with ineffective or poor efficacy of a single drug, the combination of drugs can be used to improve the effect of uric acid reduction. For example, the combination of allopurinol (200~600mg/d) and benzbromarone (100 mg/d), propoxur (0.5g/d) or RDEA594 (200~600mg/d, second generation uric acid excretory drug) at stable doses is significantly better than allopurinol alone in lowering uric acid. RDEA594 (600mg/d) combined with febuxostat (40~80mg/d) is also significantly better than febuxostat alone in lowering uric acid.
Of course, there can be other ways to combine drugs, such as between two drugs that inhibit uric acid synthesis. The combination of allopurinol (100-300 mg/d) with the purine adenosine phosphorylase inhibitor BCX4208 (20-80 mg/d) brought more gout patients to uric acid levels than allopurinol alone, and the rate of attainment increased with increasing doses of both drugs. These drugs can also be combined with drugs that have relatively weak uric acid-lowering effects.
4. Expectation of new uric acid-lowering drugs
(1) New drug to inhibit uric acid synthesis – febuxostat. It is especially suitable for patients with urinary stones that cannot be fully hydrated, excessive uric acid production, contraindication to uric acid excretory drugs and allopurinol allergy or intolerance.
(2) RDEA-594, a second-generation uric acid excretory agent, is characterized by minimal hepatotoxicity, is comparable to allopurinol in efficacy, is effective in mild to moderate renal insufficiency, has a low risk of inducing kidney stones, and has no serious adverse events.
(3) A new drug to promote uric acid decomposition – Precahi. This drug is fast in lowering uric acid and dissolving gout stones, and can be used in adult refractory gout patients for whom conventional uric acid-lowering therapy has failed. However, the high price, infusion reactions and frequent gout attacks during the initial period of use limit its widespread use.
In conclusion, refractory gout is more difficult to treat. Regardless of which uric acid-lowering drug or drugs are used, the earlier the target is reached and the more consistently it is reached, the better the prognosis is, and sustained uric acid compliance is the key to refractory gout treatment. It is worth noting that in the early stage of uric acid-lowering treatment for refractory gout, acute attacks of gout need to be prevented. On the one hand, for the first time with uric acid-lowering drugs, the dose should be gradually increased from small doses; on the other hand, small doses of colchicine (0.5mg, tid) or non-steroidal anti-inflammatory drugs can be used to prevent acute attacks, and biological agents including and anti-interleukin-1 and anti-tumor necrosis factor (TNF) alpha agents can be used for those who are ineffective to reduce the pain caused by joint attacks and to improve patient compliance.