Introduction

Gouty arthritis is an inflammatory joint disease, caused by monosodium urate monohydrate crystal, which leads to local and systemic inflammation [1]. The prevalence of gout is 1.4–3.9% in most developed countries. It is more prevalent in men and postmenopausal women, and is on the rise [2]. Hyperuricemia, defined as a serum urate level exceeding the limit of solubility (6.8 mg/dl), also predisposes affected subjects to gouty arthritis and its spectrum [3]. Elevated serum urate is associated with cardiovascular disease, hypertension, insulin resistance, metabolic syndrome, chronic kidney disease, and increased mortality [4].

Recent guidelines, ACR and EULAR, recommend treatment to reach the target serum urate level of <6 mg/dl. [5,6,7] Urate-lowering therapy is the mainstay of the treatment to achieve the target serum urate. The ACR guideline recommends allopurinol and febuxostat as the first-line therapy [5]. However, the EULAR and British guidelines both recommend allopurinol as the first-line drug and febuxostat only for refractory cases [6, 7].

Due to the high mortality rate of allopurinol hypersensitivity syndrome (AHS), ACR recommends screening for HLA-B*5801 in high-risk population [5, 8]. People of Thai descent are considered a high-risk group for AHS [5].

Febuxostat, a non-purine selective xanthine oxidase inhibitor, exhibited potent and dose-dependent urate-lowering effect. In terms of urate-lowering efficacy, febuxostat is superior to 300 mg of allopurinol and displays good safety profile in cohorts dominated by people of European descent [9, 10]. However, the data regarding febuxostat in Asian people is still limited, as well as the factors associated with successful urate control. There are few Asian studies that showed febuxostat could be safely prescribed in patients with renal insufficiency [11, 12]. Furthermore, febuxostat may also delay the progression of renal dysfunction in people with coexisting chronic kidney disease [13].

The objective of this retrospective study was to compare the efficacy of febuxostat (40 mg/day and 80 mg/day) with allopurinol (100 mg/day and 300 mg/day) in Thai people with gout. We also compared the proportion of target urate achievement in febuxostat to allopurinol. Furthermore, this study sought to determine the predictive factors for target urate achievement and to describe the safety profile of febuxostat in a real-world, resource-limited clinical setting.

Material and methods

Study design and population

The study was conducted as a retrospective cohort study of people with gout who were initiated on febuxostat or allopurinol during their follow-ups at the rheumatology service, Thammasat University Hospital, between February 2015 and November 2018. Data of people with gout who were 18 years or older were collected from physical and electronic medical records. All patients were diagnosed with gout according to the 2015 ACR/EULAR classification criteria for gout [14]. The exclusion criteria were the following: (1) chronic kidney disease (CKD) stage 4 and 5 or renal replacement therapy, (2) pregnancy or breast feeding, (3) active liver disease or liver enzymes > 1.5 times the upper limit of normal, (4) alcoholism (alcohol > 14 units/week), (5) people with missing laboratory results, and (6) any modification to medications that could affect serum urate level. These medications included allopurinol, febuxostat, probenecid, benzbromarone, sulfinpyrazone, aspirin, diuretics, losartan, fenofibrate, pyrazinamide, ethambutol, cyclosporine, and estrogen. For those started on allopurinol and febuxostat, no dose titration was applied. The patients were initiated on the dose according to their subgroup and had their medications maintained at the same dosage throughout the study.

Variables

The variables included demographics, comorbidities (impaired fasting blood glucose, diabetes, hypertension, chronic kidney disease, hyperlipidemia, fatty liver, ischemic heart, and metabolic syndrome), and history of alcohol intake and smoking. The concomitant medications, including beta-blocker, calcium channel blocker, aspirin, angiotensin-converting enzyme inhibitor (ACEI), losartan, irbesartan, statin, fenofibrate, diuretics, and anti-tuberculosis drugs, were recorded. Gout-related variables included the presence of crystal, tophus, renal stone, radiographic joint destruction, the prophylaxis of flare, the usage of uricosuric agents, and flare during the first 3 months after medication. Laboratory investigation included serum urate, creatinine, aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase. The serial serum urate (sUA) levels were recorded at the beginning of the treatment (baseline) and then at 12 weeks, 18 weeks, and 27 weeks after treatment initiation. The creatinine, AST, and ALT were recorded at baseline and 12 weeks after treatment to monitor for potential adverse drug reaction. As febuxostat is the second-line agent in our hospital, we also recorded the reason for using or switching to febuxostat. Patients were divided into four groups according to the urate-lowering agent used: allopurinol 100 mg/day, allopurinol 300 mg/day, febuxostat 40 mg/day, and febuxostat 80 mg/day. A study time table is shown in supplementary Table 1.

Efficacy endpoints

The primary efficacy endpoint was the proportion of patients who achieved sUA < 6.0 mg/dl at 12 weeks, 18 weeks, and 27 weeks after treatment in each study group [5, 6].

The secondary endpoints were the factors associated with achieving target serum urate level.

Statistical analysis

The categorical data were described as frequency and percentage, while continuous data were presented as mean and standard deviation. The comparison was analyzed using Mann-Whitney U test for continuous variables and Chi-square or Fisher’s exact test for categorical variables. A univariate binary logistic regression was used to screen for potential factor associated with achieving target serum urate. Variables with the p value less than 0.05 were included in the multivariable regression model. We reported the regression coefficients, odds ratios, 95% confidence interval, and p value for the final regression analysis. Statistical analysis was carried out using IBM SPSS Statistics version 25.

Ethical approval

The study protocol was reviewed and approved by the Human Research Ethics Committee, Faculty of Medicine, Thammasat University (reference number MTU-EC-IM-6-141/60). Informed consent is not required for this type of study.

Results

Cohort characteristics

In total, there were 354 people with gout in the cohort: The characteristics of the patients as well as comparison between study groups are listed in Table 1.

Table 1 Patient characteristics
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Compared with the allopurinol 100 group, the other groups (allopurinol 300, febuxostat 40, and febuxostat 80) had more severe disease: higher prevalence of flare per year, tophi, renal stone, and erosion or deposition by imaging study. Combination with uricosuric agent was more common in patients taking febuxostat, compared with those taking allopurinol. Statin, diuretics, and aspirin were more common in the allopurinol 100 group, compared with other groups.

One hundred and fourteen patients were prescribed with febuxostat. Inefficacy of the first-line therapy (allopurinol) accounted for 45.6% of patients, whereas adverse reactions from allopurinol were the indication in 38.6% (Table 2). Metabolic syndrome was higher in febuxostat groups than allopurinol groups (62% versus 64%). Also, CKD was found with higher percentage in febuxostat groups (57% versus 46%). From our study, we did not find adverse drug reaction in febuxostat-prescribed patients even in those with CKD.

Table 2 Indication for initiation or switching to febuxostat (n = 114)
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Achievement of target serum urate level

Mean serum urate levels at baseline were similar in all study groups. In all study groups, serum urate level continued to decrease after treatment initiation. Similarly, the proportion of people who achieved target serum urate level continuously rose. However, a significantly greater proportion of people who took febuxostat achieved target serum urate at every follow-up visit, compared with those taking allopurinol (Table 3 and Fig. 1).

Table 3 Proportion of people who achieved target serum urate level and the mean serum urate level at baseline and subsequent follow-ups
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Fig. 1
figure 1

Proportion of people achieving target serum urate level

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Logistic regression analysis

The univariate analysis revealed that six variables were associated with achieving target serum urate level: febuxostat (both 40 mg/day and 80 mg/day), baseline urate level, number of flare per year, smoking, and hyperlipidemia (Table 4). In the multivariate analysis, 40 mg febuxostat (OR = 10.96 (95% CI 4.32–27.80); p value < 0.001), 80 mg febuxostat (OR = 9.54 (95% CI 3.91–23.28); p value < 0.001), low baseline urate level (OR = 0.62 (95% CI 0.52–0.74); p value < 0.001), and smoking (OR = 2.35 (95% CI 1.13–4.91); p value = 0.23) were associated with the achievement of target serum urate (Table 5).

Table 4 Univariate regression analysis for variables associated with target serum urate achievement
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Table 5 Multivariate regression analysis for variables associated with target serum urate achievement
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Discussion

Our study showed that, in a real-world setting, febuxostat had higher urate-lowering efficacy at 12, 18, and 27 weeks compared with allopurinol. Factors associated with achieving the target serum urate at 27 weeks were the use of either 40 mg or 80 mg of febuxostat, lower baseline serum urate level, and smoking. No serious adverse event was observed. Febuxostat is a non-purine, selective xanthine oxidase inhibitor that can be prescribed as a second-line drug according to EULAR, BSR, and our Thai guideline.

Long-term studies have confirmed the efficacy and tolerability of febuxostat. [15,16,17,18] Current guidelines recommend to start with a dose of 80 mg/day and the dose could be increased for up to a maximum of 120 mg/day if necessary [19, 20]. Our study regarding the efficacy of febuxostat was in agreement with previous studies. A 28-week study to compare the urate-lowering efficacy and safety of febuxostat, allopurinol, and placebo demonstrated that febuxostat was more effective than allopurinol (100 mg/day and 300 mg/day), including for those with mild to moderately impaired renal function [21]. After 1 month of treatment initiation, more than 80% of patients receiving febuxostat 80 mg/day or 120 mg/day achieved sUA < 6.0 mg/dl, whereas only 46% of the allopurinol group did. Febuxostat also led to progressive reduction of tophi and elimination of gout flare [15]. Another study of elderly (> 65 years old) patients also showed that febuxostat was superior to allopurinol and well tolerated in the elderly with renal impairment [17]. A study from Japan found that the serum urate-lowering efficacy of febuxostat may decrease in patients with a higher previous dose of allopurinol, renal impairment, or in male patients [22]. The previous high allopurinol dose may reflect the therapeutic resistance of patients to xanthine oxidase inhibitors. Febuxostat had lower efficacy in male patients compared with female. The lower plasma concentration explained by higher body weight is presumed to contribute to the lower response in male patients [22]. Data from China, regarding predictors of poor response to ULT, found that younger age, higher BMI, and higher baseline sUA are predictors of poor response to ULT [23]. Overweight and obesity are associated with metabolic syndrome and hyperuricemia, and weight reduction is associated with better control of sUA [24]. There was data suggesting that a medical history of treatment with hyperlipidemia was a protective factor against therapeutic failure to achieve sUA. The rationale for this association might be from the relation between hyperlipidemia and hyperuricemia or only a selective bias in health-concerned patients [24]. There were many researches confirming the association between higher baseline sUA and lower achievement of sUA goal < 6.0 mg/dl [23, 25, 26]. Predictive factors of achieving the target urate in our study were febuxostat, smoking, and the low baseline serum urate. The association between initial serum urate and the achievement in our study was concordant with the previous studies. The higher response in febuxostat groups can be explained by the higher efficacy of the drug. Another possibility is the previous high allopurinol dose might reflect the resistance to xanthine oxidase inhibitors. Our cohort agrees with previous studies, which found that the resistant groups were the patients with high serum uric acid, higher allopurinol dosage, renal insufficiency, and metabolic syndrome [13, 22,23,24,25]. Additionally, data showed that patients who switched to febuxostat from allopurinol had a significantly higher likelihood of attaining sUA goal of lower than 6.0 mg/dl compared with patients who maintained on allopurinol [23, 25]. We could not find plausible mechanism to explain how smoking could be an indicator of a better sUA outcome.

The result from our study demonstrated a good safety profile of febuxostat, despite a proportion of people having coexisting renal insufficiency. Febuxostat, which is metabolized mainly in the liver, had shown efficacy and tolerability in patients with renal impairment in large studies [16,17,18, 27,28,29]. In Asian people specifically, febuxostat also showed a generally good safety profile [11,12,13], even in hemodialysis patients. [30, 31]

There were some limitations in our study. First, the study was a retrospective study which might be subjected to selection bias. Second, the number of patients was relatively small and the patients were all from a referral center which might not reflect a primary care setting, where a large proportion of gout patients are treated. On the other hand, a study based on participants from a resource-limited, real-world setting is currently lacking. Our study provides an additional insight into this little-studied population.

In conclusion, febuxostat has higher urate-lowering efficacy and generally good safety profile compared with allopurinol in an Asian cohort of gout patients. Febuxostat, smoking, and the low baseline serum urate were associated with the achievement of the target serum urate level of < 6 mg/dl at 12, 18, and 27 weeks of treatment. In patients with inadequate response to allopurinol or allopurinol hypersensitivity, febuxostat may be considered an effective and safe alternative option.