Introduction

A decreased renal urate excretion is the predominant driver of attracting gout, an auto-inflammatory arthritic disease that may develop secondary to hyperuricemia [1, 2]. There is an interest in effective urate-lowering therapies with a uricosuric mode of action. This applies in particular for gout patients in whom urate production inhibitors such as the xanthine oxidase inhibitors (XOi) allopurinol and/or febuxostat are failing or induce side effects [2]. The development of safe uricosurics has been complicated for decades [3] as only benzbromarone and probenecid were approved and selectively marketed in only specific countries [1–3]. During the last decade, novel uricosurics were developed, and specific targets were discovered blocking intrarenal urate transporter 1 (URAT1) and/or organic anion transporter 3 (OAT3) or OAT4 URATs. Pharmaceutics produced drugs manipulating URAT1 aiming to improve benzbromarone: lesinurad [4, 5], verinurad [6], and dotinurad [7]. After a short period of marketing of lesinurad, the latter was withdrawn because of limited selling and safety issues, and the whole uricosuric pipeline appeared a frozen one [8]. Suddenly in 2022, a lack of source material for benzbromarone became a predominant issue, so patients stable while using this drug were left (partially) untreated. We, therefore, wish to learn lessons from our experience within 98 real-life gout patients who had a valid indication for benzbromarone in the Dutch setting with first choice gout therapy for the XOi allopurinol (1st) and febuxostat (2nd). We studied whether calculating a fractional excretion of uric acid (FeUA) may be of value to clinicians using this mode of action therapeutically.

Materials and methods

Results

Patients inclusion

Our electronic database comprised of 1,186 gout patients, all diagnosed within 5 years. We detected 100 patients who were treated to target with an (add-on) uricosuric: benzbromarone 100 mg quaque die (QD) as first choice, if not tolerated, there was a temporary availability of the uricosuric drug lesinurad 200 mg QD second choice. Two patients used lesinurad (due to early intolerance for benzbromarone: severe diarrhea) and 98 patients benzbromarone; the latter group on benzbromarone was included for further analysis into this study, see flow diagram Figure 1 for the design of the inclusion process. The uricosuric treatment was add-on at different time points in the therapeutic process aiming for a treat to target at 6 months.

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Figure 1. 

Flow diagram—selection process for patients’ inclusion

Patients were 70 (± 12) years of age, and 90% were male. Gout symptoms were reported 8.0 (± 6.5) years before the initial diagnosis. A standard dose of benzbromarone 100 mg QD was prescribed in 81 patients; 70 patients were not on target (< 0.36 mmol/L) using XOi monotherapy and were given an add-on combination therapy with benzbromarone. The baseline characteristics are given in Table 1. Benzbromarone was prescribed during a period of 4.1 (± 5.9) years interquartile range (IQR; 0.04‒9.9) of treatment in 70% of cases in combination with an XOi (allopurinol or febuxostat).

Table 1.

Baseline characteristics of 98 patients indicated for benzbromarone

Patient characteristics	N (%)
Sex
-Male	8 (90%)
-Female	10 (10%)
Duration of symptoms prior to inclusion
-Years (SD)	8.2 (6.5)
Age
-Mean (SD)	70 (12)
Initial dose of benzbromarone
-50 mg QD	15 (15%)
-100 mg QD	81 (83%)
-200 mg QD	2 (2%)
Initial combination therapy
-With allopurinol	67 (68%)
-With febuxostat	3 (3%)
Initial sUA
-Mean (SD), mmol/L	0.45 (0.12)
Initial eGFR
-Mean (SD), mL/min	54 (18)

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SD: standard deviation

Discussion

The main conclusion from this retrospective study comprising 98 patients treated with benzbromarone either in mono- or combination therapy with XOi was that 69% reached the sUA target < 0.30 mmol/L (5 mg/dL) and 91% reached a level < 0.36 mmol/L (6 mg/dL) target irrespective of low or non-low excretor status. Similar results were reported with the selective URAT1 inhibitor dotinurad [4]. In the present study patients with a high sUA level, a low FeUA, and adequate GFR had the best effect size when using this mode of action. In low excretors, FeUA increased by about +9%, whereas in non-low excretors, FeUA excretion remained stable. Only 70% of these non-low excretor-type gout patients achieved the sUA < 0.36 mmol/L target versus 92% of the low excretors. In addition, most side effects were found in the group of patients with a non-low FeUA.

Gout patients can be characterized by clinical manifestations of arthritic attacks with hyperuricemia plus a low urate excretion due to either low GFR or, more specifically, low FeUA [1, 2]. We here demonstrate from a retrospective cohort that subdivision into low versus non-low (normal to high) FeUA status may help clinicians to find the right profile for uricosurics: a low FeUA may increase by factor 4 using a potent uricosuric such as benzbromarone, which enables achieving lower biochemical sUA targets; moreover, the tolerance of benzbromarone appears to be best in these low-excretors. In real life gout patients benzbromarone is stopped either after a period of successful debulking or from late-onset intolerance or adverse events: liver toxicity (1%) and/or loss of renal function (4%) or renal lithiasis (1%). These may well be considered class specific [3–6].

The therapeutic approach in gout, in general, is a dietary limitation of purines and/or urate production inhibitors by XOi, i.e., allopurinol or febuxostat. Their doses are being escalated to reach a predefined clinical and biochemical target [1, 2]. If escalated doses are not tolerated, or targets cannot be achieved, then uricosurics may be considered, i.e., probenecid in the USA and benzbromarone in some European countries including the Netherlands, Spain, Germany, as well as Brazil [2, 3]. Efficacy or safety data from these older drugs come from small studies only. We here showed from an inception cohort that the uricosuric benzbromarone effectively increases urate excretion, particularly in cases with an a priori low FeUA in combination with an adequate renal function. Regarding serious adverse events, we found that using benzbromarone, these side effects occurred in 6% of cases, particularly in patients with an initial higher FeUA from the outset and it hardly occurs in patients with a low excretor status. This may well point to a specific patient profile for optimal efficacy and safety of the potent uricosuric benzbromarone. Further prospective studies powered by GFR and FeUA are needed to find the optimal profile if uricosurics are considered.

Probenecid is a benzoic acid derivative used in gout treatment since 1952 [9, 10]. It is an inhibitor of predominantly urate excretion transporters, the so-called OAT1 and OAT3, a renal tubular transporter facilitating enhanced urate excretion by blocking re-uptake [9–11]. Probenecid is associated with 18% gastrointestinal adverse events, 5% hypersensitivity and rash, and 1 in 3 become intolerant with, therefore, discontinuation of the probenecid. In Europe, probenecid had proven efficacy when suddenly benzbromarone was withdrawn from the market [12, 13]. Benzbromarone is a benzofurane and a potent uricosuric used in gout treatment over the last 30 years but restricted to only a limited number of countries [13]. It inhibits the urate exchanger in the human proximal tubule URAT1, reducing urate reabsorption and potently lowering sUA. Clinical trials showed efficacy (predominantly sUA lowering and reduction of attacks) and safety of benzbromarone [3, 11–16], also in patients with decreased renal function as long as GFR > 20 mL/min, showing effectivity in monotherapy [15, 16], and when in combination therapy with allopurinol or febuxostat [17, 18].

Benzbromarone is considered a potent and safe uricosuric [19]. In our study, serious adverse events were seen more often in patients characterized as non-low, i.e., normal or high excretors, in combination with decreased kidney function. No major safety concerns were raised while using dotinurad, in a small group of patients in Japan [20]. So far, the FeUA has hardly been measured in studies of novel uricosurics, whereas it is the core parameter of their mode of action. We here showed a 3.8-fold increase in FeUA with benzbromarone in low excretors, whereas only 1.3-fold in non-low excretors with about 1 in 3 not achieving the sUA < 0.30 mmol/L (5 mg/dL) as the target. Interestingly, over the last years, European Medicines Agenc (EMA) and Food and Drug Administration (FDA) made lesinurad 200 mg QD available for gout patients irrespective of their FeUA, but lesinurad was withdrawn from the market because of low market penetrance. Lesinurad was an oral selective inhibitor of the renal urate reabsorption transporters URAT1 and OAT4 [5]. Lesinurad 200 mg dose elevated the FeUA 3.6-fold, reduced sUA by about 30% [4], not inhibiting glucose transporter 9 (GLUT9) nor ATP-binding cassette G2 (ABCG2) [5, 21], and showed a low risk for mitochondrial toxicity induction (unlike benzbromarone), and not inhibiting OAT1 nor OAT3 (unlike probenecid). Lesinurad in a monotherapy setting had similar issues as benzbromarone: deterioration of renal function and lithiasis occurring up to 5%-class-specific side effects [6]. In the clinical studies (CLEAR/CRYSTAL), FeUA was not measured for lesinurad, so here we cannot learn whether high excretor status was a predictor for worse outcomes from these studies [22, 23]. The willingness to incorporate FeUA into a study design was recently done in the short-term verinurad study where FeUA was calculated [7]. Another study using FeUA for classifying gout patients as underexcretors showed a 60% success rate of benzbromarone in achieving a target sUA level < 0.36 mmol/L [24]. Lesinurad monotherapy 400 mg and 600 mg QD demonstrated class-specific renal side effects in about 5–10% [21] and verinurad showed these in 11.6%. Whether these are associated with higher FeUA status is unclear as these data were not provided. In future studies, it may be crucial for all patients in studies to complete a full urate profile metabolism, including FeUA prior and after uricosuric therapy. This may indicate towards a specific group of patients who can benefit the most from this specific medication and at the same time may help prevent renal side effects.

In conclusions, we learned from retrospective benzbromarone data that efficacy and safety are best if prescribed in low excretor gout patients, with over 90% achieving a 0.30 mmol/L sUA target. If targets cannot be reached in gout patients, an add-on uricosuric may be considered, particularly in low excretors.