Intensive reduction of serum uric acid with uricase effect through the combination of benzbromarone and febuxostat in patients with difficult-to-treat tophaceous gout

 

Claudia María Gómez-González, Marta Novella-Navarro, Fernando Pérez-Ruiz, Enrique Calvo-Aranda

 

Affiliation(s):

Rheumatology resident in rheumatology department, hospital Universitario Infanta Leonor

 

 

Background: Some patients with gout have multiple comorbidities and subcutaneous tophi refractory to conventional monotherapy with urate-lowering treatments (ULT). Uricases may be helpful drugs, but they are not always available. Combined treatment with two potent ULT, such as FBX and BNZ, could achieve a uricase-like effect and be a therapeutic alternative for these patients.

Objectives: To evaluate the efficacy and tolerance of the combined treatment of benzbromarone BNZ with FBX in patients with difficult-to-treat (D2T) tophaceous gout. 

Methods: Multicenter observational study with patients diagnosed with gout according to EULAR/ACR 2015 criteria, subcutaneous tophi, and poor response to standard of care treated with a combination of BNZ and FBX according to a 12-month two-step regimen: FBX monotherapy for the first 6 months (individualized dose optimization), followed by subsequent addition of BNZ (50 mg/day, progressively escalating to 100 mg, whenever possible). Demographic and clinical variables related to gout, cardiovascular risk factors (CVRF), nephrolithiasis, estimated glomerular filtration rate (eGFR), and liver enzymes were collected. A descriptive analysis of the sample was performed using frequencies and percentages for qualitative variables and measures of central tendency and dispersion for quantitative variables. T-test for paired samples was used to analyze changes in uric acid (UA) levels and eGFR. 

Results: Fifteen patients were recruited from two hospitals, 87% male, with a median age of 59 years (range 43-93), oligo/polyarticular arthritis and a mean of 5.7±3.7 attacks in the year before starting BNZ. Most of them had advanced gout (mean 16.2±8.8 years), with high basal UA levels (mean 10.3±1.7 mg/dl), a marked presence of CVRF (93% hypertension, 73% dyslipidemia, 13% major cardiovascular event, 7% diabetes), and renal impairment (mean eGFR 63.7±23.6 ml/min; mean creatinine 1.21±0.37 mg/dl). Only one patient had a history of nephrolithiasis. Before starting combination therapy, 80% had received monotherapy with a xanthine oxidase inhibitor: 27% allopurinol (median 200 mg/day, range 100-300), 53% FBX (median 100 mg/day, range 40-120). Adding BNZ to FBX treatment resulted in a significant reduction in UA at 12 months (Δ=2.1 mg/dl [95CI: 1.2- 2.9], p<0.001), in addition to the initial decrease achieved by FBX alone (Δ=2.3 mg/dl [95CI: 1.1-3.6], p=0.002; figure 1), with tophi dissolution in 60% (9/15) of patients. The median duration of follow-up was 18 months (range 9-44); median exposure to BNZ 12 months (range 6-38). Reasons for discontinuation of BNZ were tophi dissolution in nine patients, loss of follow-up in three patients and poor clinical tolerance in one patient. There were no serious adverse events, renal colic or significant changes in liver enzymes or kidney function after 12 months compared to baseline values (eGFR12m 61.6 vs eGFRbaseline 63.7 ml/min; n.s.). One death was recorded (no treatment-related; elderly, history of aortic regurgitation). 

Conclusion: In our sample, the combination of BNZ and FBX was effective in patients with D2T tophaceous gout, with an intensive reduction in UA and rapid tophi dissolution. Combined therapy was well-tolerated by most patients.