The rates of prevalence of asymptomatic hyperuricemia and gout, caused by prolonged hyperuricemia, are increasing throughout the world (Putterman, 1991; Hakoda, 2012; Kuo et al., 2015; Elfishawi et al., 2018; Hakoda and Kasagi, 2019; She et al., 2022). Based on accumulating evidence, the Japanese Guidelines for Management of Hyperuricemia and Gout, 3^rd edition, recommend administration of urate-lowering drugs (ULDs) for patients with asymptomatic hyperuricemia complicated by renal disease as well as gout patients in addition to lifestyle modification (Hisatome I et al., 2020). Allopurinol, febuxostat, topiroxostat, benzbromarone, probenecid, and dotinurad have been approved and are used as ULDs in Japan.

Variations in serum urate levels and gout attacks related to season of the year have been reported, with most studies showing higher urate levels and a greater proportion of gout attacks in summer and autumn (Elliot et al., 2009; Karmacharya et al., 2016; Akerblom et al., 2017; Romaszko et al., 2022). Those findings suggest that the frequency and degree of hyperuricemia are higher in summer and autumn, thus the frequency of gout attacks is consequently also higher in summer and autumn. However, no real-world data have been presented regarding whether ULD prescriptions in daily clinical practice for asymptomatic hyperuricemia and gout also have seasonal variations.

Using a large medical claims database of cases in Japan, the present study was conducted to investigate seasonal variations in prescriptions of ULDs for treatment of asymptomatic hyperuricemia and gout by determining the numbers of monthly prescriptions of new ULDs for asymptomatic hyperuricemia and gout.

This is the first known study to investigate seasonal variations in prescriptions of ULDs for asymptomatic hyperuricemia and gout. The findings showed seasonal variations of new prescriptions for ULDs, as they were significantly more common in summer and autumn as compared winter, with no notable difference after stratification by disease type, drug type, and medical institution, or subgrouping by age and sex (Figures 2–4). On the other hand, as compared to winter, new ULD prescriptions for asymptomatic hyperuricemia were significantly lower and for gout significantly higher in spring.

Previous reports have noted differences regarding proportion and persistence of ULD prescriptions for asymptomatic hyperuricemia and/or gout, as well as type and cost (Hakoda and Kasagi, 2019; Peng et al., 2019; Koto et al., 2021; Akari et al., 2022). However, no real-world data on the seasonality of ULD prescriptions have been presented. The present study indicates that new prescriptions of ULDs for asymptomatic hyperuricemia and gout are seasonal, with higher rates of prevalence in summer and autumn (Figures 2, 3), with no remarkable difference found following stratification of the results based on asymptomatic hyperuricemia and gout (Figures 3, 4). These findings suggest a relationship with seasonal onset of asymptomatic hyperuricemia and gout, as clinicians prescribe ULDs for those conditions more often in summer and autumn.

Seasonality in regard to serum urate levels and onset of gout attacks has been reported. A study of urate levels in more than 170,000 blood samples from a Swedish adult population showed higher levels in those obtained in summer (Akerblom et al., 2017), with other similar findings also presented (Goldstein et al., 1972; Letellier and Desjarlais, 1982; Murciano Revert et al., 2000). In addition, a study that examined serum urate in 54,536 blood specimens from a Polish laboratory showed higher levels in autumn samples (Romaszko et al., 2022). In regard to the seasonality of gout incidence, a large study that analyzed surveillance data for 920,000 patients found that new cases of gout were more frequent in summer (Elliot et al., 2009), which has been confirmed in other similar reports (Goldstein et al., 1972). In addition, a study of 28,172 patients admitted to a hospital with a primary diagnosis of acute gouty arthritis showed that gout onset was more common in autumn (Karmacharya et al., 2016). Together, these findings suggest that onset of asymptomatic hyperuricemia and gout is more common in summer and autumn, thus new prescriptions for ULDs are also more common during those seasons.

Age and sex are known to be strongly associated with hyperuricemia and gout (Hakoda and Kasagi, 2019; Singh and Gaffo, 2020; Zitt et al., 2020). Consistent with those reports, the proportion of ULDs prescribed in the present study was higher for middle-aged and older as compared with younger patients, and for males as compared with females (Figure 4). However, no significant effect of age or sex was observed in regard to the seasonality of ULD prescription proportions (Figure 3), suggesting some common factors causing seasonal differences independent of age and sex. Differences in ambient temperature and alcohol consumption may account for the higher proportion of new ULD prescriptions for asymptomatic hyperuricemia and gout in summer and autumn as compared to winter. A higher ambient temperature increases the risk of dehydration, which is known to be a factor associated with increased serum urate level through increased purine catabolism and decreased urinary excretion of uric acid (Yamamoto et al., 2004b; Kakutani-Hatayama et al., 2017; Kuge et al., 2017). Consistent with those reports, ambient temperature has been found to be positively correlated with frequency of gout attacks (Neogi et al., 2014). On the other hand, high consumption of alcoholic beverages has been reported to be associated with development of hyperuricemia and gout (Choi et al., 2004a; Wang et al., 2013; Makinouchi et al., 2016; Teramura et al., 2023). Alcoholic beverage consumption is known to increase the level of serum urate due to uric acid production from adenine nucleotide breakdown and decreased uric acid excretion through lactic acid production, in addition to intake of purines contained in those beverages (Yamamoto et al., 2004a; Ka et al., 2005; Yamamoto et al., 2005). Notably, among alcoholic beverages, consumption of beer has been shown to be strongly associated with increased serum urate level and gout (Choi et al., 2004a; Choi and Curhan, 2004; Singh et al., 2011; Zykova et al., 2015), and also to have a correlation with ambient temperature because of higher levels of consumption in summer (Silm and Ahas, 2005; Kaminski et al., 2021). Thus, higher ambient temperature and increased alcohol consumption, especially beer, in summer and autumn as compared to winter may increase the incidence of asymptomatic hyperuricemia and gout in summer and autumn, resulting in new ULD prescriptions more commonly seen in those seasons.

Following stratification by asymptomatic hyperuricemia and gout, new ULD prescriptions for asymptomatic hyperuricemia were significantly lower and for gout significantly higher in spring as compared to winter, whereas those in summer and autumn were similar for both groups (Figure 3). Some previously reported smaller studies noted that onset of gout is more common in the spring (Schlesinger et al., 1998; Choi et al., 2020), though, to the best of our knowledge, there have been no reports indicating that serum urate levels are higher or lower in spring. In Japan, many workplace transfers of patients as well as doctors occur in April, during which a treating physician may refrain from prescribing new ULDs for asymptomatic hyperuricemia patients without symptoms. On the other hand, gout is a painful disease and new ULDs for gout may be more commonly prescribed regardless of workplace transfer issues. Thus, the presence or absence of symptoms may be an important issue affecting the discrepancy regarding new ULD prescriptions in spring between asymptomatic hyperuricemia and gout. Alternatively, factors that cause gout but not hyperuricemia may be present during that season. Additional studies regarding prescription patterns, as well as development of hyperuricemia and gout in the spring will be needed.

As for the significant seasonality regarding new ULD prescriptions shown in subgroup analyses by age and sex, that was also noted with medical institution stratification (Figure 3). The present results suggest that because Japan has a universal health insurance system that allows patients to visit any medical institution and receive medical treatments without restriction, new-onset patients with asymptomatic hyperuricemia or gout were seen regardless of the medical institution, resulting in similar seasonality among the institutions. On the other hand, the Japanese Guidelines for Management of Hyperuricemia and Gout, 3^rd edition, recommend administration of ULDs not only to patients with gout but also those with asymptomatic hyperuricemia complicated by renal disease, though not to patients affected by hypertension or heart failure (Hisatome I et al., 2020), in contrast to Western guidelines, such as the 2020 American College of Rheumatology Guideline for the Management of Gout, which does not recommend UDL administration for patients with asymptomatic hyperuricemia (FitzGerald et al., 2020). Further studies are needed to determine the impact of these guidelines on pharmacological management including seasonality of ULD prescriptions for patients with asymptomatic hyperuricemia and gout as a part of clinical practice.

The present study has several important limitations. First, the commercially available JMDC data used in the present study allows extraction of only numbers of patients by age, sex, ICD-10 diagnostic code, and prescription details, thus other information for individual cases could not be obtained. As result, adjustment of results of the present study by use of confounding factors, including age, sex, disease type, coexisting conditions, concomitant medications, and medical institutions, could not be performed. In addition, information related to time-variable characteristics such as coexisting conditions in each patient could not be obtained. Consequently, the study was limited to subgroup analyses based on time-invariant characteristics. Second, the JMDC data used do not include information for individuals aged 75 and older, since those are automatically enrolled in a medical program for elderly and data regarding new ULD prescriptions for such patients were not available. Third, factors not examined included serum urate level, ambient temperature, and alcohol intake, as well as data for degree of obesity, physical activity level, and dietary intake of meat, seafood, fructose, and dairy products, known to be associated with serum urate level and gout (Takahashi et al., 1997; Yamamoto et al., 1997; Choi et al., 2004b; Kaya et al., 2006; Kurajoh et al., 2011; Kurajoh et al., 2020). Fourth, though Japan extends for a long distance from north to south and weather patterns vary considerably in different regions, seasons are classified according to the Japan Meteorological Agency classification and the same throughout the country. Since we were not able to extract region-specific data from the commercially available JMDC data for the present study, analyses that take into account monthly average temperature by region were not performed. Fifth, the number of female patients newly prescribed ULDs was noticeably lower than that of male patients, possibly because new prescriptions for ULDs for treating asymptomatic hyperuricemia and gout are less common in female cases. Inequalities in enrolment of women in clinical trials of ULDs have been reported (Fogacci et al., 2021), which is an issue that should be considered in future studies related to prescription of such drugs. Finally, we defined patients with a code M10 and with/without a code E79.0 as affected by gout, while those with a code E79.0 and without a code M10 were defined as affected by asymptomatic hyperuricemia. However, the distinction between asymptomatic hyperuricemia and gout based on ICD-10 codes may differ from the actual situations, because of the possibility of incorrect entry of the codes or other such errors. Large-scale and more detailed investigations will be necessary to better elucidate the reasons for seasonality of new ULD prescriptions. Nevertheless, the present results obtained by examination of a large dataset of more than 200,000 patients indicate that new prescriptions for ULDs for asymptomatic hyperuricemia and gout are seasonal, and significantly more frequent in summer and autumn.

In conclusion, the present results showed new ULD prescriptions for asymptomatic hyperuricemia and gout were significantly greater in summer and autumn, with no notable difference after stratification by disease type, drug type, and medical institution, or subgrouping by age and sex. These findings suggest that because of seasonal variations in occurrence of asymptomatic hyperuricemia and gout, for which ULDs are routinely prescribed, new ULD prescriptions are more common in summer and autumn in Japan. On the other hand, new ULD prescriptions for asymptomatic hyperuricemia were significantly lower and those for gout significantly higher in spring than winter. It will be necessary to conduct further studies to clarify prescription patterns, as well as factors related to development of hyperuricemia and gout in the spring.