Real-world treatment of gout and asymptomatic hyperuricaemia in Japan.

Abstract

Recently a retrospective cohort study in Japan conducted by Koto et al. disclosed that the risk of the first gout flare would decrease 55% if serum uric acid was reduced to 5–6 mg/dl among people with asymptomatic hyperuricaemia receiving uric acid–lowering drugs as compared with untreated people (serum uric acid ≥ 8.0 mg/dl) [1]. Another study by Koto et al. published in Modern Rheumatology using the same database disclosed that the prevalence of gout was about 1.1% in Japan [2], which was lower than Taiwan (3.1%) [3].The authors commented that the low prevalence of gout in Japan could be attributed to the early drug treatment of asymptomatic hyperuricaemia based on the Japanese guideline [2, 4]. Both studies by Koto et al. provide the evidence that the natural course of asymptomatic hyperuricaemia can be changed by the intervention of uric acid–lowering drugs. Some points are discussed. First, hyperuricaemia and gout are closely related but are not the same disease. Most of the people with hyperuricaemia do not develop a gout flare during their lives [5]. Whether people with asymptomatic hyperuricaemia should take uric acid–lowering drugs to prevent the first gout flare, the academic community has not yet established a consensus. The American College of Rheumatology guideline suggests against the use of uric acid–lowering drugs to treat asymptomatic hyperuricaemia [6]. The Japanese guideline suggests that the treatment goal of hyperuricaemia is to prevent monosodium urate deposition in joints and viscera, not only leading to the risk reduction of gout flares but also leading to the risk reduction of organ damage and then leading to prolonged disease-free survival, especially cardiovascular diseases [4]. After lifestyle modification, if serum uric acid is still ≥ 9.0 mg/dl, clinicians may talk to people with asymptomatic hyperuricaemia about the current evidence of managing hyperuricaemia and possible adverse events of uric acid–lowering drugs, such as hepatotoxicity, urinary stones, and cutaneous adverse reactions. Only after informed consent is obtained, clinicians are able to consider prescribing uric acid–lowering drugs to those suitable patients [4]. Although serum uric acid ≥ 9.0 mg/dl is an independent risk factor for gout flares, there have been no randomized control studies focusing on the management of asymptomatic hyperuricaemia where the primary endpoint was set as the development of the first gout flare. Therefore, in the current situation, urate-lowering drugs are not strongly recommended for asymptomatic hyperuricaemia in order to prevent the first gout flare. Moreover, in the present guidelines, how to treat hyperuricaemia should be decided after assessing the patients’ concomitant diseases. Second, benzbromarone is a uricosuric drug to lower serum uric acid. Because of its potential hepatotoxicity, benzbromarone had been withdrawn from some markets since 2003, but it still can be prescribed in many countries including Taiwan and Japan [7]. Three case reports in Japan showed that benzbromarone could be related to fulminant hepatotoxicity, but none was confirmed by rechallenge tests [8–10]. However, no hepatotoxicity was reported in Taiwan and South Korea. Allopurinol is the first drug of choice to lower serum uric acid in western countries [6]. Allopurinol use has a potential risk to cause severe cutaneous adverse reactions. Among the three Asian countries, the incidence rate of allopurinol-related severe cutaneous adverse reactions was the highest in Taiwan (2.57/1000 person-years), followed by South Korea (2.31/1000 person-years), and the lowest in Japan (2.00/1000 person-years) [11]. In ethnic groups with a high frequency of HLA-B*5801, benzbromarone will be safer than allopurinol for the management of hyperuricaemia. The standard doses of benzbromarone (100 mg/day) are more effective in lowering serum uric acid than the standard doses of allopurinol (300 mg/day) [12]. Only higher doses of allopurinol (450 mg/day) are as equally effective in lowering serum uric acid as the standard doses of benzbromarone (100 mg/day) [12]. Third, current guidelines do not present which drug should be the first-line drug for asymptomatic hyperuricaemia. If we want to set up a new clinical guideline, it is necessary to determine which drug is more effective and safer to prevent the first gout flare in people with asymptomatic hyperuricaemia. It indicates a future research direction.