Early Serum Urate Level Improvement Linked with Response to Febuxostat in Males with Gout

Male gout patients’ responses to low-dose febuxostat are linked to early serum urate level (sUA) improvement, according to recent findings, and they are additionally linked with patients’ body mass index (BMI), age, and levels of triglycerides (TG) and C-reactive protein (CRP).¹

These findings resulted from new research led by investigators in China, conducted for the purposes of improving understanding of the predictors of inadequate response (IR) to treatment with low-dose febuxostat using clinical variables.

This research was led by Wenyan Sun from Shandong Provincial Key Laboratory of Metabolic Diseases at Shandong Provincial Clinical Research Center for Immune Diseases in Qingdao, China. Sun et al. highlighted that those treated with ULT require additional titration ULT regimens based on timing of ambulatory encounters, preferences, and other elements in the treatment of gout.²

“Based on individual participant data from available trials, this study aimed to investigate the predictors associated with inadequate serum urate response to low-dose febuxostat during early ULT in pooled patients with gout,” Sun and colleagues wrote.

Background and Methods

The investigators drew their participants from a prospective observational cohort of individuals with gout who had been treated with 20 mg of febuxostat and had been monitored every 4 weeks with the aim of evaluating the predictive ability of CA-724. The team also included 2 randomized controlled trials (RCTs), with 1 assessing the effectiveness and safety of chitosan oligosaccharide treatment, and the other comparing low-dose benzbromarone with low-dose febuxostat among gout patients.

All subjects had been given a regular 20 mg febuxostat dose for a total of 12 weeks. The investigators determined their criteria for inclusion to be males in the age range of 18 or older with gout, those who had been given at least 12 total weeks of febuxostat, and those with available clinical, demographic, and follow-up interaction information.

The research team defined inadequate responders as subjects who were not able to reach the target sUA level of below 6 mg/dL at any point within the team’s short-term or mid-term follow-up meetings. The team also gathered participants’ baseline clinical, biological, demographic, and radiological data among each cohort, using a clinical evaluation to assess tophi.

If they found any discrepancies among the laboratory data between the cohorts, they only retained the common variables. There were a total of 218 samples used with relatively complete data over 29 variables for the investigators’ discovery dataset.

Machine learning models were also utilized by the team to assess such predictors, with the team implementing the pooled data as the discovery set and validating against an external test set.

Findings

There were 340 total participants in the investigators’ study, with 68.9% and 51.8% having been non-responders to the low-dose of febuxostat within the short- and mid-term follow-up groups, respectively.

The investigators found that triglyceride (TG) and serum urate levels had been substantially associated with febuxostat IR. Additionally, these levels were determined by the team as major elements through their LASSO analysis as well as BMI, age, and C-reactive protein (CRP).

Through the best-performing stochastic gradient descent classifier used by the investigators, the research team were able to reach an area under the receiver operating characteristic curve of 0.873 (95% CI [0.763, 0.942]) as well as 0.706 (95% CI [0.636, 0.727]) within their internal and external test sets, respectively, as febuxostat IR predictors.

“These findings suggested a stratified treatment regimen for patients with gout,” they wrote. “The robust ML prediction model for inadequate serum urate response may allow the identification of patients who are likely to require dose escalation of febuxostat to achieve the serum urate target.”

References

1. ^{Sun W, Zhao X, Dalbeth N, Terkeltaub R, Cui L, Liu Z, Han L, Wang C, Zhang H, Bao Y, Li C, Lu J. Predictors of Inadequate Serum Urate Response to Low-Dose Febuxostat in Male Patients with Gout. J Inflamm Res. 2024 Apr 30;17:2657-2668. doi: 10.2147/JIR.S458250. PMID: 38707960; PMCID: PMC11069377.}
2. ^{FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American college of rheumatology guideline for the management of gout. Arthritis Care Res. 2020;72(6):744–760.}