Urate-lowering therapy for gout and asymptomatic hyperuricemia in the pediatric population: a cross-sectional study of a Japanese health insurance database

Gout and asymptomatic hyperuricemia are treated to reduce the painful symptoms of gouty arthritis and gout tophi, and also to prevent the development of gout-related kidney disease and uric acid kidney stones. In pediatric patients with persistent hyperuricemia, dual-energy computerized tomography scans show urate crystal deposition very similar to that seen in adults with persistent hyperuricemia [1‐3]. However, the causes of hyperuricemia in adult patients are more often related to lifestyle, while hyperuricemia in pediatric patients is usually due to underlying chronic disease, including cardiovascular and kidney disease, and to inborn errors of metabolism [4‐15].

In a previous study, we accessed a Japanese health insurance database to study the incidence and prevalence of gout and of asymptomatic hyperuricemia in children and to investigate patient characteristics in that population [16]. To the best of our knowledge, that report was the first description of pediatric gout and asymptomatic hyperuricemia in a real-world clinical setting. Our findings showed that a certain number of pediatric patients had gout or asymptomatic hyperuricemia and that the prevalence of these conditions increased with age. In particular, many pediatric patients with gout or asymptomatic hyperuricemia also had cardiovascular disease and/or kidney disease. After puberty, we also noted an increase in the number of patients with comorbid metabolic syndrome associated with lifestyle-related diseases [16].

We also found that urate-lowering therapy (ULT) was frequently prescribed for pediatric patients with gout or asymptomatic hyperuricemia, even though those drugs have not yet been approved for pediatric indications in Japan [16]. In adult gout patients, ULTs are typically prescribed to prevent the development of gouty arthritis by reducing serum uric acid levels to < 6.0 mg/dL [17‐21]. In general, pediatric studies tend to have markedly fewer patients than studies in adults, and each drug formulation and dosage must be investigated in each age group within the pediatric population. These factors, which contribute to delays in drug development, also apply to gout and hyperuricemia in pediatric patients. As a result, ULT is not yet internationally approved for gout or hyperuricemia in children, and there is almost no mention of pediatric gout or hyperuricemia in treatment guidelines in Europe and the United States [17, 18]. There are thus very few reports of ULT to treat hyperuricemia in pediatric patients with gout, and the real-world status of such treatment has not been clearly documented.

Unlike Europe and the United States, Japan considers the risk of gouty arthritis in hyperuricemic individuals, and ULT is recommended for adults with asymptomatic hyperuricemia who do not have a history of gout but do have serum uric acid ≥8.0 mg/dL and renal or cardiovascular comorbidities, as well as for otherwise healthy patients who have serum uric acid ≥9.0 mg/dL [19, 20]. However, almost no research has been published on how these adult treatment conditions affect therapeutic interventions in hyperuricemic children, particularly those with asymptomatic hyperuricemia.

The present cross-sectional study builds on our previous work [16], using data gathered from medical database records of patients who were covered by Japanese health insurance. Our objective was to examine the real-world clinical treatment of pediatric patients with gout or asymptomatic hyperuricemia in Japan. This type of information is needed to determine what kinds of treatments are appropriate for gout and asymptomatic hyperuricemia in children.

Most of the methodology of this study has been reported previously [16] and is summarized here.

In this study we investigated the real-world use of ULT for gout and asymptomatic hyperuricemia in children. Even at low prescription levels, we found that the ULT was selected after considering patient characteristics including patient’s comorbidities, that dosage and administration were based on the experience of real-world usage in adults, and that continuous serum uric acid management was tried in pediatric patients with gout or hyperuricemia in much the same way as in adults.

Japan has a universal health insurance system to which all Japanese residents subscribe for comprehensive health insurance through their employer or an administrative agency. The cost of covered medical care is the same across the country, the co-pay for the patient is usually 30% of the total medical cost, and most local governments also offer free or discounted health care to children. Every citizen can be seen at any medical facility at any time, and various biochemical tests are performed during the process of diagnosis at those facilities. In these tests, which are covered by health insurance, the standard test panel usually includes uric acid. Thus, the Japanese healthcare system provides an environment in which hyperuricemia can be detected at a high rate and ULTs are easy to prescribe for those patients.

In the present study, we found that the highest proportion of ULT was prescribed to patients who had kidney or cardiovascular disease. In these patients with hyperuricemia and cardiovascular disease, we found a notable age-related increase in ULT prescriptions. In the kidney disease subgroup, the proportion of ULT use was particularly high in patients aged 6–11 and 12–18. Because the kidneys excrete uric acid, serum uric acid elevation is generally expected in patients with kidney disease, whether children or adults, and some papers have been published on the relationship between kidney disease and serum uric acid level [14, 26, 27]. Our study confirmed that pediatric patients with hyperuricemia and kidney disease were prescribed ULT, and our results were consistent with previous reports. ACEI/ARBs were used by 24.7% of the patients prescribed ULT, in comparison to 4.5% of patients not prescribed ULT. ACEI/ARBs are often prescribed for kidney or cardiovascular disease [28, 29], and these conditions may cause serum uric acid levels high enough to require treatment. However, it remains unclear whether ACEI/ARBs elevate serum uric acid levels.

The subgroup with underlying metabolic syndrome contained the highest number of diagnosed patients, but the proportion receiving ULT was lower than for other comorbidities. The lower level of ULT in those patients may have been because this syndrome is treated primarily by lifestyle changes, and ULT is generally prescribed only if lifestyle changes are insufficient to manage the patient’s condition.

In the Down syndrome group, 40.0% (6/15) received ULT. All 6 were 12–18 years of age, and 5 had multiple comorbidities of kidney disease, cardiovascular disease, or metabolic syndrome. Particular caution is required from puberty, at which time Down syndrome patients begin to experience increasingly high risk of hyperuricemia [12], in part because the comorbidities of lifestyle-related diseases and obesity predispose to uric acid elevation. There have been some cases in which juvenile gouty arthritis occurred in patients with Down Syndrome [11], and that background may also be related to these comorbidities.

Our study showed that febuxostat and allopurinol were the most commonly prescribed ULTs in pediatric patients. In children, MPRs for these drugs were similar to the proportion reported in adults [25]. These findings indicated that ULT was being prescribed for continuous serum uric acid management in pediatric patients in much the same way as in adults. Analysis of mean prescribed doses of febuxostat and allopurinol in pediatric patients showed that approximately half the mean prescribed dose for adults was used in patients aged 6–11 and the same amount in patients aged 12–18 [25]. This may be because the dosage for children was based on that for adults, since dosage and administration have not been established for pediatric use. The number of patients on febuxostat was highest in the kidney comorbidities subgroup, possibly because allopurinol is eliminated by the kidneys [30], while febuxostat has both hepatic and renal elimination routes [31].

In pediatric patients, chronic hyperuricemia is often associated with underlying conditions, such as cardiovascular or renal diseases, inborn errors of purine metabolism, genetic disorders, or kidney transplantation [4‐15]. In contrast, hyperuricemia in adult patients is often associated with sexual differences or lifestyle-related diseases. Serum uric acid levels are known to increase with age in male children because of the effects of increased testosterone levels [4], and our previous study showed both age-based and sex-based differences in the prevalence of hyperuricemia [16]. We also found a relationship between age and metabolic syndrome [16], suggesting that adolescent hyperuricemia may be associated with lifestyle-related diseases [32, 33]. Based on the findings above, we hypothesized that the prevalence of hyperuricemia and gout increase because of overlapping factors or effects of changes in age or lifestyle during the transition from childhood to adulthood.

Particularly in patients with underlying conditions as described above, such as inborn errors of metabolism, congenital heart disease, and congenital kidney disease, chronic hyperuricemia can develop at a young age and may result in gout before the child reaches 10 years of age. This situation places an enormous burden on patients and their families. There are several case reports of pediatric gout patients who had familial juvenile hyperuricemic nephropathy or other comorbidities and whose gout became intractable in their 20s or 30s, resulting in joint deformity or tophus [8‐10, 34, 35]. Recent years have seen increasing concern about the incidence of gout and asymptomatic hyperuricemia in children, and the potential onset of gouty arthritis at younger ages, as a result of obesity [32, 33]. Previously, we reported that the risk of gouty arthritis is similar in pediatric and adult gout patients [16] and those findings emphasize the potential importance of drug therapy for pediatric patients with gout or asymptomatic hyperuricemia in whom lifestyle modification has been insufficiently effective. In such cases, ULT might prevent the deposition of urate crystals and progression to refractory disease that could occur if hyperuricemia remains untreated into adulthood [36, 37].

Because this was a database study, we were unable to investigate serum uric acid levels at the start of therapeutic intervention and after treatment, or to collect data on safety. In the near future we hope that clinical studies will be performed in pediatric patients to determine the relationship between dosage and uric acid level, to investigate the safety and tolerability of ULTs, and to establish effective drug therapy for gout and asymptomatic hyperuricemia in this population.

This study has several limitations. First, we analyzed data based on information from insurance claims (medical fee claim forms), which were not collected for research purposes, so the validity of definitions for various diseases was not assured. Second, the overall study population was less than 300 patients, and several subgroups contained only a few patients, which limits the generalizability of our findings. Third, data used were from company employees and their family members, which excluded members of other populations, reducing our findings’ generalizability. Fourth, some patients had claims reimbursed through a bundled payment plan, and only limited information may have been available on prescriptions for those patients. Fifth, this was a cross-sectional study with evaluation during a single period, so it was impossible to estimate the causal relationship between exposure and outcome.

Our study analyzed the use of ULTs in pediatric patients with gout or hyperuricemia, based on data from a Japanese health insurance claims database. Results show that the off-label use of ULTs is being explored in these patients, with drug selection based on patient characteristics and dosage based on usage experience in adults. In pediatric patients, serum uric acid management tends to be continuous, and pediatric prescriptions for ULT tend to increase with patient age, particularly in male patients and those with kidney disease. Clinical trials are needed in the near future on the efficacy and safety of ULTs in the pediatric population to establish appropriate pediatric drug therapy.