Study design and participants

All gout patients diagnosed from January 2015 until March 2021 were identified from the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD10) coding system, and data were retrieved and entered anonymously in a Castor Electronic Data Capture (EDC) database by the first author. Patients’ medical data was used in agreement with the ethical consent form of the hospital.

The inclusion criterium was the ICD10 code M10 for gout. Diagnoses were based on identifying monosodium urate crystals via polarized light microscopy and/or meeting the ACR/EULAR 2015 classification criteria for gout [3]. There were no specific exclusion criteria for this study. Therefore, all patients who met the inclusion criteria were included in the analysis.

Patients’ data were collected and stored anonymized for analysis with SPSS version 26. We collected demographic data, clinical variables, and laboratory parameters at baseline after 6 months and 12 months of follow-up. Age, sex, family history of gout, duration of symptoms, body mass index (BMI), clinical comorbidities (cardiovascular disease, diabetes mellitus type 2, dyslipidemia, renal disease), and medication data were collected. The comorbidities were defined based on prespecified diagnoses as described in the medical files. Obesity was defined as a BMI over 30 kg/m², and cardiovascular disease was considered as history of ischemic heart disease or hypertension (blood pressure > 140/90 mmHg; 18/11 kPa). Renal disease/disorder was defined as a glomerular filtration rate (GFR) of less than 60 mL/min. Laboratory assessment included sUA and creatinine, estimated GFR (eGFR), mL/min per 1.73 m².

The main outcomes of this study were the efficacy of urate lowering therapy (ULT) achieving the ACR target of sUA ≤ 0.36 mmol/L (6 mg/dL) or the stricter sUA ≤ 0.30 mmol/L (5 mg/dL) respectively at 6 months and 12 months after initiation of the ULT. Some patients were seen only once at consultation and did not show up for follow-up visits, and therefore cannot be analyzed.

According to the sUA levels in patients with an intention to treat follow-up, we distinguished 3 patient groups:

• (1).

  Group 1: sUA ≤ 0.36 mmol/L but > 0.30 mmol/L (ACR/EULAR target for gout [1]).

• (2).

  Group 2: sUA ≤ 0.30 mmol/L (ACR/EULAR target for severe gout [1]).

• (3).

  Group 3: sUA > 0.36 mmol/L (failure to meet any ACR/EULAR target).

The dosage of ULTs that were analyzed were noted at 6 and 12 months. The numbers of patients and the comorbidities with particular reference to the clusters defined by Richette et al. [3] were noted. Additionally, we analyzed sex differences in outcomes.

Statistics

Baseline characteristics and adherence to therapy are presented as mean ± SD values. Differences between groups were compared using an independent t-test for continuous variables and a chi-square test (χ²) for categorical variables. Associated factors for reaching the sUA target were analyzed using linear regression. The odds ratio (OR) was presented with a 95% confidence interval (CI), and P < 0.05 was considered statistically significant. Analysis was done using SPSS software version 26 and Graph Pad Prism 7.

Patient characteristics

We identified 1,186 patients with gout who met the 2015 ACR-EULAR classification criteria: 986 (83%) males and 200 (17%) females. Baseline characteristics are given in Table 1.

A microscopically crystal proven diagnosis of gout was made in 976 cases (82%) using compensated polarized light microscopy (CPLM) analysis. There were 204 patients (17%) classified as tophaceous; 210 (18%) were not microscopically crystal-proven patients but they did fulfill the ACR-EULAR classification criteria for gout [3]. Of 1,186 gout patients, 70% suffered from cardiovascular or other cardiovascular comorbidities: hypertension in 33%, dyslipidemia in 42%, renal disease (eGFR < 60 mL/min) in 37%, and type 2 diabetes in 21.4%.

Treatment

All patients were given written dietary advice poor in purines, limited use of (malt) beers and fructose-enriched drinks, and, if possible, increased coffee use. The written dietary advice was also explained orally.

ULT escalation regimes were only prescribed by rheumatologists. No ULT prescription was given before the consultation. In 95% of patients, a urate lowering drug was prescribed at the baseline visit. Allopurinol was prescribed in 882 cases (87%), and adherence at 6 months was strict in 808/1,009 (80%) patients. Febuxostat was the 2nd choice alternative and thus started in 48 (4.7%). Benzbromarone was prescribed in 98 (8.2%) patients, indicated because of a previously proven and/or experienced allopurinol/febuxostat intolerance. The combination of allopurinol/febuxostat plus benzbromarone was prescribed in 70 patients (5.9%). Of these patients, 78% achieved the predefined target < 0.30 mmol/L at 6 months vs. 51% of patients who followed allopurinol in monotherapy (Figure 1).

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Figure 1. 

Outcome regarding achieving the predefine target of serum urate level at 6 months using the three urate lowering therapies in monotherapy or in combination setting

Numbers of patients for analysis in the groups at 6-month follow-up

We started with 1,186 gout patients, and 73 (6.1%) were lost at 6-month follow-up (plus/minus 1 month); 50 males (79.3%) and 23 females. At the 6-month time slot (plus/minus 1 month), we had data from 1,113 patients (Figure 2):

• (1)

  Group 1: Treat to sUA between 0.30 and 0.36 mmol/L; n = 292 (26.2%); 241 males (82.5%) and 51 females (17.5%).

• (2).

  Group 2: T2T sUA < 0.30 mmol/L; n = 564 (50.7%); 472 males (83.6%) and 92 females (16.3%).

• (3).

  Group 3: Failure to reach target 0.36mmol/L; n = 257 (23.1%); 223 males (86.7%) and 34 females (13.2%).

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Figure 2. 

Flow diagram

Follow-up after 6 months up to 12 months in the combined groups 1 and 2 (T2T groups reaching sUA ≤ 0.36 mmol/L)

In groups 1 and 2, the adherence to ULT options was similar, and significant changes were not found between the proportion of patients receiving ULTs at 6 months vs. 12 months. At 6 months and 12 months, a substantial number of patients (n = 65 and n = 64, respectively) required a combination of ULTs to get to the stricter target sUA ≤ 0.30 mmol/L. At 12 months, allopurinol was used by 84.5% of patients, benzbromarone by 9.9%, and febuxostat by 8.8%, and the combination of XOi plus uricosuric was prescribed in 67/792 cases (8.4%).

The dose of allopurinol varied between 50 mg to 900 mg quaque die (QD). Allopurinol 300 mg QD was the predominant dose, and in 51% of patients, this dosage was still used at both 6 months and 12 months follow-up. With allopurinol 300 mg QD, the target sUA ≤ 0.36 mmol/L was reached in 42.2% (n = 123) of patients after 6 months of therapy. The stricter sUA ≤ 0.30 mmol/L target was achieved in 45.5% of cases (n = 255). With allopurinol 100 mg QD (n = 11), 3.8% of patients reached the ≤ 0.36 mmol/L target; and 2.6% (n = 15) reached the sUA ≤ 0.30 mmol/L target.

A strong correlation was found between the prescribed dose of allopurinol and achievement of reaching the stricter sUA ≤ 0.30 mmol/L target at 6 months: r = −0.1795, 95% CI (−0.2558, −0.101), P < 0.001. The use of benzbromarone was strongly associated with reaching the sUA ≤ 0.30 mmol/L target at 6 months: vs. no benzbromarone OR 3.2, 95% CI (1.735, 6.017).

At 6 months, 856 patients (77%) reached the serum urate ≤ 0.36 mmol/L target. Within this group, there was a positive correlation between the allopurinol dose at 6 months and the eGFR: r = 0.233, P < 0.0001. There was a negative correlation between allopurinol dose and serum urate level at 6 months: r = −0.153 (P = 0.0001). At 6 months, over 90% of patients were using allopurinol treatment, and it was noted that the eGFR in these patients had improved slightly but significantly: +8.6 mL/min per 1.73 m² (P = 0.0005), 95% CI (1.423, 9.941). This was not observed in patients treated with febuxostat or benzbromarone. No difference between these groups was found in using corticosteroids or a potentially nephrotoxic medication, i.e., NSAIDs. There was no significant difference in GFR at baseline in the group of patients using benzbromarone vs. allopurinol.

Febuxostat was only dosed in 80 mg QD. In this group, 50% had a decreased renal function, and 33% was tophaceous. With febuxostat monotherapy (n = 54), 9.5% reached the ≤ 0.36 mmol/L target and 12.3% (n = 36) the ≤ 0.30 mmol/L target.

Prophylactic medication was advised and prescribed in 75.6% (647) of cases: predominantly colchicine in 66.1% (427) and/or prednisone in 39.6% (256).

Despite prophylactic treatment, gouty attacks were reported spontaneously by 7 (0.1%) patients on febuxostat and 59 (7.2%) on allopurinol during 6 months of ULT treatment.

Group 3: patients failing to reach the 0.36 mmol/L target

In our study, 257 patients (23%) did not reach the 0.36 mmol/L target at 6 months. At the 6-month visit, 73% of patients still adhered to ULT medication. In this category, the lowest percentage of uricosurics was used (5.2% vs. 12.7% in category 2). A significant difference we found was a lower starting dose of allopurinol of 100 mg in category 3 compared to categories 1 and 2 (P < 0.0001). In this category, 3.4% had decreased renal function, and 27% had diabetes. Here we included 104 (40%) patients who chose a “treat to avoid symptoms” target in a shared decision-making process, specifically focusing on treating the attacks. These patients were treated with allopurinol 100 mg QD, and this dose decreased the sUA level by 0.19 mmol/L.

Comorbidities that may impede reaching the sUA target

Regarding comorbidities in our cohort, decreased renal function was negatively associated with reaching sUA ≤ 0.30 mmol/L target at 6 months [OR 0.692; 95% CI (0.098, 0.035)]. A history of diabetes was also negatively associated with sUA ≤ 0.30 mmol/L target at 6 months [OR 0.652; 95% CI (0.001, 0.139)]. There was no correlation between the presence of tophi, initial sUA level, and the sUA ≤ 0.30 mmol/L target at 6 months.

In our study, 216 (18.2%) patients have no comorbidities. Looking into different clusters of patients based on the presence of specific comorbidities, i.e., patients with fewer comorbidities, obese gout patients, patients with predominance of diabetes, dyslipidemia, and patients with cardiovascular and renal failure, as described previously by Richette et al. [3], we observed that the effectiveness of ULT at lowering sUA did not differ between the defined clusters (data not shown).

Diabetic patients, however, present the highest proportion of patients not getting to target (18%).

Sex differences

The mean age was 66.2 years for male vs. 75.2 years for female gout patients. The mean sUA level at initial presentation was 0.51 mmol/L in males vs. 0.47 mmol/L in females (P = 0.67). After 6 months and 12 months of treatment, there was no significant difference between the sexes regarding the mean sUA level or the reached sUA target: 70.0% of females reached < 0.36 mmol/L vs. 72.3% of males (P = 0.42). To reach the predefined target, females needed a lower dose of allopurinol: on average, 238 mg QD in females vs. 334 mg QD in males (P = 0.0001; Figure S1).