Urate crystal arthritis, or gout, is the most common cause of non-traumatic joint inflammation, and its prevalence and incidence have been increasing in recent decades [1]. Gout results from elevated serum urate (SUA) levels that exceed the saturation threshold and persist over time, leading to the nucleation, growth, and accumulation of monosodium urate (MSU) crystals in tissues. Gout is a debilitating disease that significantly impacts patients’ quality of life and ultimately leads to functional impairment [2, 3].

Pharmacological treatment of gout using the treat-to-target (T2T) approach with urate-lowering treatments (ULTs) aims to dissolve MSU crystal deposits by reducing SUA levels to < 6 mg/dL (< 5 mg/dL in severe gout) [4]. The current standard of care (SoC) consists primarily of monotherapy with xanthine oxidase inhibitors (XOIs), such as allopurinol (ALO, usually the first-line ULT) or febuxostat (FBX). Uricosurics, including benzbromarone (BNZ), lesinurad (LSN), and probenecid (PBN), may also be used when available. Pegloticase, a recombinant uricase with a strong hypouricemic effect, is typically reserved for severe XOI-refractory tophaceous gout or in cases with contraindications [5, 6]. However, its use is limited by availability, cost, and infusion-related reactions [7].

Although the combination of XOIs and uricosurics is included in international gout management guidelines [5, 6], the few studies that have assessed its efficacy and safety mostly involved ALO [8–19]. Combination therapy with two potent ULTs, such as FBX and BNZ [BNZ being more widely available than LSN (withdrawn from the European market) and better tolerated than PBN at medium-high doses] [20], may be a therapeutic alternative for patients with severe gout, which is characterized by large subcutaneous tophi, recurrent attacks, and comorbidities. Severe gout is also referred to as difficult-to-treat (D2T) gout or D2T gouty arthritis, based on criteria used in clinical trials that led to European Medicines Agency approval of canakinumab for gout (≥ 3 attacks per year and contraindications, refractoriness, or intolerance to SoC) [21–23].

This was an observational study including patients with severe D2T gout treated at the Hospital Universitario Infanta Leonor (HUIL), Madrid; and Hospital Universitario Cruces (HUC), Barakaldo. All patients met the 2015 European Alliance of Associations for Rheumatology/American College of Rheumatology (EULAR/ACR) classification criteria for gout [24], had subcutaneous tophi, and poor therapy to SoC with XOI monotherapy. Poor therapy was defined as insufficient resolution of tophi and/or ≥ 3 gout attacks in the previous 12 months despite prophylactic treatment with non-steroidal anti-inflammatory drugs (NSAIDs), colchicine, or glucocorticoids [21–23]. Patients with severe renal impairment, active liver disease, or previous allergy or intolerance to FBX or BNZ were excluded. Combination therapy in this study was based on FBX rather than ALO, as FBX was selected for its greater urate-lowering potency and favorable pharmacokinetics, especially in patients with mild-to-moderate renal impairment, which is common in severe gout.

The treatment protocol was agreed upon prospectively by both centers based on prior clinical experience. It consisted of a two-step regimen: an initial 6-month phase comprising escalation of the dose of FBX, followed by the addition of BNZ with progressive uptitration. For patients already receiving FBX, the dose was increased to the highest tolerated level. For new FBX users, treatment was initiated at 40 mg/day with progressive escalation to the maximum tolerated dose. In the second phase, BNZ was added to FBX in all patients at 50 mg/day, with escalation to 100 mg/day if tolerated (aiming for higher doses to enhance urate lowering and tophus resolution). All patients received colchicine (0.5 mg/day) prophylaxis for at least 12 months to reduce the risk of attacks, in accordance with international recommendations [5, 6]. Prednisone or low-dose NSAIDs were used as alternatives in patients with intolerance. Despite prophylaxis, any gout flares occurring during follow-up were managed according to those recommendations, using NSAIDs, colchicine, glucocorticoids, or interleukin-1 (IL-1) blockers as clinically appropriate, based on patient factors and preferences.

Demographic, clinical, and laboratory data were collected. These included cardiovascular risk factors (CVRFs), major cardiovascular events (MACEs: myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization), history of nephrolithiasis, estimated glomerular filtration rate (eGFR), and liver function test results. Clinical evaluations included joint examination and tophi measurement (caliper, ultrasound, and, in selected cases, spectral computed tomography). Tophi resolution was evaluated using the same methods during follow-up visits. Blood tests were performed at baseline, month 1, and then every 3 months. Adherence to therapy was monitored using institutional electronic pharmacy dispensing records.

Descriptive analyses were performed using frequencies and percentages in the case of qualitative variables. For quantitative variables, measures of central tendency (mean or median) and dispersion [standard deviation (SD) or interquartile range (IQR)] were reported based on the data distribution. A paired samples t-test or a Wilcoxon test was performed to assess changes in quantitative variables. Statistical analyses were performed using SPSS version 21.0, and significance was set at p < 0.05.

The study was approved by the Ethics Committee of OSI EEC at Cruces University Hospital (CEIC-E03/45) and adhered to the principles of the Declaration of Helsinki. Written informed consent was obtained from all participants.

Data on 15 patients [HUC 9, HUIL 6 (87% male)] were collected from a database of over 2,000 patients. The median age was 59 years (range, 43–93), and the mean number of attacks per year was 5.7 ± 3.7. Disease was longstanding (median duration 15 years, range 3–31, IQR 8–25), baseline SUA was high (mean 10.3 ± 1.7 mg/dL), and the prevalence of CVRFs was high (hypertension, 93%; dyslipidemia, 73%; MACE, 13%; diabetes, 7%). Impairment of kidney function varied (mean eGFR 63.7 ± 23.6 mL/min; one patient had a history of nephrolithiasis). Baseline demographic and clinical characteristics are presented below (Table 1).

All patients had received SoC but were unable to control inflammation despite receiving ULT and prophylactic treatment (colchicine, NSAIDs, or prednisone). Several patients required tetracosactide or anakinra. Before initiating FBX + BNZ, 80% had received XOIs [27% ALO (median 200 mg/day; range 100–300), and 53% FBX (median 100 mg/day; range 40–120)]. At three months, FBX doses were 80, 120, and 160 mg/day in 11, 3, and 1 patients, respectively. At six months, the doses were 80, 120, and 160 mg/day in 2, 12, and 1 patient, respectively. BNZ was then added, increasing from 50 to 100 mg/day, with 73% receiving 100 mg/day by the end of follow-up.

After a median follow-up of 18 months (range, 9–44), all patients completed the first 6-month phase of treatment (FBX monotherapy). Median BNZ exposure to BNZ was 12 months (range, 3–38), with 93.3% (14/15) of patients receiving BNZ for at least 6 months.

In this study, standard-dose FBX/BNZ combination therapy was well tolerated by patients with severe D2T gout, leading to a significant reduction in SUA and rapidly dissolving tophi. ULT aims to prevent attacks and eliminate tophi by lowering SUA. While SoC includes XOIs (ALO or FBX) and uricosurics (BNZ, PBN, and LSN), some patients remain refractory or intolerant to conventional treatment [21, 25].

No unified and validated term has been proposed for D2T gout. However, the condition is certainly prevalent and poses a therapeutic challenge. Globally, the T2T strategy has proven successful in gout; however, some patients with severe tophaceous D2T gout require stringent SUA targets (< 5 mg/dL, ideally < 4 mg/dL) for complete dissolution of MSU crystals [26–28]. This also has significant implications for prognosis, given the link between tophi and mortality [29, 30].

Most patients in our study met intended SUA targets with the ‘FebBenz’ approach at 12 months (80% < 5 mg/dL, 73.3% < 4 mg/dL) and end of follow-up (93.3% < 4 mg/dL, 33.3% < 3 mg/dL). Achieving such a reduction often necessitates combination therapy, as XOIs decrease uric acid formation while uricosurics enhance excretion [5]. Beyond efficacy, uricosurics may confer endothelial benefits in hyperuricemia [31].

However, unlike other inflammatory arthropathies such as rheumatoid arthritis, where the combination of several drugs is common, studies on ULT combinations in gout are scarce, focusing primarily on ALO [8–19]. Although both drugs have demonstrated significant efficacy as monotherapy in patients affected by gout, with BNZ being superior to PBN, studies on the FBX + uricosuric combination, typically at low doses, suggest superior efficacy [12, 17, 18]. Xue et al. [13] reported enhanced urate-lowering with FBX + BNZ, positioning this combination therapy as a potential alternative to standard ULT regimens [20, 32]. Our study revealed an even greater reduction in SUA (10.3 to 2.7 vs. 9.4 to 5.6 mg/dL) with higher doses (FBX 80–160 vs. 20–40 mg/day, BNZ 50–100 vs. 25 mg/day) and longer follow-up [18 (9–44) vs. 3 months]. Our cohort had older patients [59 (43–93) vs. 40 (32–46) years], all with tophi (100% vs. 17%), and a longer disease duration (mean 16 vs. 4 years), higher baseline SUA (mean 10.3 vs. 9.4 mg/dL), greater prevalence of CVRFs (hypertension, 93% vs. 23%; dyslipidemia, 73% vs. 43%; diabetes, 7% vs. 5%; major adverse cardiovascular events, 13% vs. 4%), and worse renal function (eGFR 63.7 ± 23.6 vs. 100.2 ± 14.1 mL/min).

Compared with Xue et al. [13], we recorded a higher loss to follow-up (20% vs. 12%) [13]. However, our safety outcomes were favorable, with no serious adverse events or significant changes in renal or hepatic function, even with prolonged exposure to BNZ [12 (3–38) vs. 3 months] and the use of higher doses of FBX + BNZ (see above). Notably, initial XOI therapy mitigates the renal urate burden (SUA × GFR) more effectively than initial treatment with a uricosuric agent. Additionally, stepwise addition of uricosurics enables monitoring of SUA and assessment of the risk of nephrolithiasis (via urine pH and urine uric acid levels). In our cohort, no nephrolithiasis events were reported.

Lastly, with LSN withdrawn, the ‘FebBenz’ approach may be a cost-effective alternative to uricases (pegloticase/rasburicase), which are limited by cost, availability, and immunogenicity [33].

The strengths of our study include its multicenter design, homogeneous baseline characteristics (severe tophaceous gout, high SUA, and failure of SoC), real-world D2T patient data (including middle-aged and elderly patients, with a high prevalence of CVRFs, chronic kidney disease, and other comorbidities), ambitious SUA targets, and the longest reported follow-up for ULT combination therapy.

Our study is limited by its observational design, small sample size, and losses to follow-up (influenced by the COVID-19 pandemic, BNZ supply shortages, and patient multimorbidity) [27], which may prevent generalizability. Nevertheless, the statistically significant reduction in SUA (p < 0.01) corresponds to clinically meaningful outcomes (resolution of tophi in 60%). While the uncontrolled design prevents causal inferences, the mechanistic plausibility of the synergistic action of FBX + BNZ supports our findings. Future randomized trials with adjusted analyses for confounders are needed to validate these results and evaluate long-term efficacy and safety.

In conclusion, we found the combination of FBX + BNZ to be effective and well-tolerated in patients with D2T gout, resulting in intensive reduction in SUA and rapid dissolution of tophi. The combination of FBX + BNZ may serve as a therapeutic alternative for patients with severe gout.