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Seminars in Arthritis and Rheumatism

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Combination urate-lowering therapy in the treatment of gout: What is

the evidence?
D1X XFernando Perez-RuizDa,
2X X *, D3X XNicola DalbethDb4X X
a
Rheumatology Division, Hospital Universitario Cruces, University of the Basque Country, Bilbao 48903, Spain
b
Bone and Joint Research Group, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand

TAGEDPA R T I C L E I N F O TAGEDPA B S T R A C T

Background: Combination therapy that includes a uricosuric and xanthine oxidase inhibitor (XOI) is recom-
mended in guidelines for patients with gout who do not meet treatment targets with XOI monotherapy
Keywords:
alone. While the use of combination therapies has been investigated for many years, we reviewed data from
Gout
Combination therapy the published studies to investigate the efficacy and safety of this approach.
Serum uric acid Methods: Relevant published papers were identified by keyword search on PubMed and categorized accord-
Uricosurics ing to the types of combination therapies included. Study methods and results were summarized. Outcomes
Xanthine oxidase inhibitors of combination therapy were compared with respective monotherapies, where possible.
Results: Efficacy was assessed by changes in serum urate (sUA), urinary uric acid, gout flare rates, and /or
tophi. Safety assessments, where reported, included adverse events and, for more recent studies, laboratory
assessments. Early studies in the 1960s based on case reports or open-label designs and more recent, well-
designed studies with large patient numbers provided consistent outcomes: that combination therapy with
a uricosuric and a XOI provides substantially greater sUA lowering than achieved by either monotherapy.
Greater sUA lowering translated to greater gout symptom control, including improved tophus resolution.
Conclusions: Combination therapy with a uricosuric and an XOI offers additional sUA lowering compared to
monotherapy alone and can provide benefit for achieving therapeutic targets in patients with gout who do
not achieve target sUA or are intolerant of XOIs at appropriate monotherapy dosing.
© 2018 Elsevier Inc. All rights reserved.

Introduction: current standards of care
Gout is the most common cause of inflammatory arthritis with an
increasing prevalence worldwide [1,2]. The development of gout in
most patients is associated with a persistent elevation of serum urate
(sUA) levels, which leads to deposition of monosodium urate crystals
in the musculoskeletal and other tissues and can if inadequately
treated produce recurrent acute flares, chronic arthritis, joint dam-
age, and disfiguring tophi [3 5].
Management guidelines from expert bodies recommend attaining
a sustained reduction in sUA levels below 6 mg/dL, or 5 mg/dL in
patients with severe disease [6 10]. A long-term reduction in sUA
below these levels leads to the dissolution of monosodium urate crys-
tals, which in turn reduces gout flare rates and resolves tophi
[11 14]. The extent and the velocity of tophus resolution are related
to the level of sUA lowering achieved [13,15] (Fig. 1).
The most effective method to achieve sUA lowering below target
levels is by using urate-lowering therapies (ULTs) [16]. The most
Abbreviations: AE, adverse event; eGFR, estimated glomerular filtration rate; OATs,
organic anion transporters; sCr, serum creatinine; sUA, serum urate; TEAE, treatment-
emergent adverse event; ULT, urate-lowering therapy; XOI, xanthine oxidase inhibitor.
* Corresponding author.
E-mail address: fperezruiz@telefonica.net (F. Perez-Ruiz).
widely used ULTs fall into two groups: (1) xanthine oxidase inhibitors
(XOIs; allopurinol and febuxostat), which reduce the body's produc-
tion of urate, and (2) uricosurics (including probenecid, benzbromar-
one, sulfinpyrazone, and lesinurad), which increase excretion of uric
acid by inhibiting its reabsorption in the kidney [17] (Fig. 2). In most
patients with gout, the primary cause of elevated sUA is abnormally
low uric acid excretion and so uricosuric treatment in these patients
effectively increases uric acid excretion [18 21].
Allopurinol and febuxostat are recommended in guidelines as
either first- or second-line ULTs in patients with gout [6 9]. Doses of
allopurinol a purine analog are increased in increments of
50 100 mg until an sUA of less than 6 mg/dL is attained. The mini-
mum effective maintenance dose of allopurinol varies between indi-
viduals, while the maximum dose following dose escalation is
800 mg or 900 mg (according to local guidance). Febuxostat is
approved in daily doses of 40 mg and 80 mg in the USA, and to
120 mg daily in Europe and other countries. For patients not achiev-
ing target sUA using an XOI alone at the initial selected dose, guide-
lines recommend dose uptitration to an appropriate dose as selected
by the treating physician according to the patient's profile [6 8]. In
the case of allopurinol, few patients receive doses >300 mg [22,23].
Clinical trial evidence shows that »45% of patients treated with allo-
purinol alone (in most cases, at a dose 300 mg) and »30% treated

https://doi.org/10.1016/j.semarthrit.2018.06.004
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Fig. 1. Mean sUA levels vs velocity of reduction of tophi. There is a linear relationship between the two parameters: r = ¡0.62, r2 = 0.48; p < 0.05 (From Perez-Ruiz et al with permis-
sion [13]).

with febuxostat alone fail to achieve target sUA [22,24]. For these
patients, management guidelines recommend switching to uricosuric
monotherapy or combining an XOI with a uricosuric [7,8].
Clinical trial data on uricosuric monotherapy in gout are limited
[25]. Several uricosurics probenecid, benzbromarone, and sulfinpy-
razone were developed for other indications and were first used in
gout management over 60 years ago. The predominant mechanism of
action for these three uricosurics is via inhibition of the URAT1 trans-
porter [20,26,27], which is responsible for most of the reabsorption of
filtered uric acid in the kidney [28,29]. Probenecid and sulfinpyrazone
additionally inhibit the organic anion transporters (OATs) 1 and 2,
which contributes to the drug interactions observed [30,31].
Lesinurad and verinurad are novel “selective uric acid reabsorp-
tion inhibitors”, with chemical structures distinct from the older uri-
cosurics and each other. Both have been investigated in preclinical
and clinical studies. Lesinurad inhibits OAT4 in addition to URAT1,
while verinurad is a specific inhibitor of URAT1 [20,32,33]. Lesinurad
is approved in the United States and the European Union at a 200 mg
daily dose in combination with an XOI for the treatment of hyperuri-
cemia associated with gout in patients failing to achieve target sUA
on an XOI alone, based on the results of phase III trials [34 38]. A
fixed-dose combination of lesinurad and allopurinol is also approved
in the United States in doses of lesinurad 200 mg/allopurinol 300 mg
and lesinurad 200 mg/allopurinol 200 mg. Verinurad is in clinical
development in combination with an XOI for the treatment of hyper-
uricemia associated with gout [39 41].
Arhalofenate is a product candidate for gout treatment that both
lowers sUA (via inhibition of URAT1) and reduces gout flares (by
blocking urate crystal-induced release of interleukin-1b). Arhalofen-
ate was first developed to treat components of the metabolic syn-
drome, when it was also observed to reduce sUA [42]; it has been
investigated in gout in combination with febuxostat in a phase II
study [43].
Combining agents with complementary mechanisms of action is a
widespread approach in other medical specialties, such as the long-
term management of hypertension and type 2 diabetes, where com-
bination therapy may be necessary for disease control [44 46]. In
gout, combinations of an XOI with a uricosuric have been investigated
€ and Gutman, Goldfarb and Smyth, and Kuzell
since the 1960 s (e.g., Yu
et al. [47 49]. This approach has the advantage that a dual mecha-
nism of action i.e., reduction in urate production and increased uric
acid excretion provides greater sUA lowering than achieved by a
single agent alone at the same dose. A second potential advantage is
that combination therapy may offer an alternative especially in
patients who do not achieve target sUA with XOI monotherapy or are
intolerant of XOIs at higher monotherapy dosing. In addition,
whereas uricosurics as monotherapy may be associated with
increased incidences of renal adverse effects related to their

Fig. 2. Uric acid pathway and action site of urate-lowering therapies. Drugs in italics are in development or not approved. Dashed arrow represents lack of metabolic step in
humans, due to evolutionary loss of uricase enzyme. PNP, purine nucleoside phosphorylase; XO, xanthine oxidase (Adapted from Sattui and Gaffo with permission [80]).

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mechanism of action, this risk is reduced by the concomitant decrease
in uric acid production with co-administration of XOIs. The evidence
that supports these potential advantages is discussed below.
This review article assesses the clinical trial evidence for the role
of combination therapies in gout, based on literature review and
interpretation, with a focus on sUA lowering and gout symptom
reduction.
Literature search and data presentation methodology
PubMed, web search engines, management guidelines, and
Cochrane databases were searched from inception to February 2018
to identify publications including relevant data, using the key search
terms: gout, hyperuricemia, urate-lowering therapy, uric acid, urate,
combination treatment, allopurinol, benzbromarone, febuxostat, lesi-
nurad, probenecid, verinurad, and arhalofenate. Pegloticase was not
included in the searches, as combination therapy with other ULT is
not recommended with this agent. All papers meeting the search cri-
teria, regardless of study design, are described in this review (Fig. 3).
As the focus of this review is the comparative efficacy of combina-
tion treatments, the efficacy data for each study are provided in sum-
mary tables, while the outcomes from the studies are interpreted in
the following text. Safety data for drug combinations and respective
single agents are summarized where the studies provide this infor-
mation.
XOI XOI combination therapy
Allopurinol febuxostat
A single case report was identified that describes allopurinol in
combination with febuxostat [50]. An elderly man with severe gout
and a longstanding history of hypertension and severe chronic kidney
disease (estimated glomerular filtration rate [GFR] 13.7 mL/min/1.73
m2) was treated long-term with benzbromarone alone, then benzbro-
marone combined with allopurinol (50 mg/day), benzbromarone
combined with febuxostat (60 mg/day), and finally all three agents in
combination, which successfully achieved an sUA <6.0 mg/dL. All
tophi disappeared after 3 months of combined treatment. There is no
evident rationale for combining febuxostat and allopurinol unless
differential binding to the oxidized and reduced forms of XO contrib-
uted [51,52]. It may be observed that the allopurinol dose used
(50 mg/day) was notably low, the use of benzbromarone in the pres-
ence of severe renal impairment is at least questionable (benzbro-
marone has uricosuric efficacy in patients with GFR > 20 mL/min/
1.73 m2), and only the addition of 60 mg/day febuxostat to allopurinol
had any meaningful effect on urate levels and therefore tophi. In
Fig. 3. Numbers of relevant studies identified in database searches.
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relation to safety, the authors note that: “No obvious adverse events
were reported during the combination therapy.”
Benzbromarone XOI combination therapy
Benzbromarone allopurinol
Studies with a range of trial designs were published from 1977 to
2014 on the efficacy of combined benzbromarone and allopurinol rel-
ative to allopurinol alone or benzbromarone alone in patients with
gout or hyperuricemia.
Combination therapy in these studies consistently provided
greater sUA lowering than the comparator monotherapy at the same
or similar dose [13,53 56]. In an observational study from Brazil
(n = 48 patients), treatment and dose were selected on a case-by-case
basis [54]. sUA was lowered by all three treatments, but combined
allopurinol and benzbromarone or benzbromarone alone provided a
significantly greater effect than allopurinol alone. sUA fell within the
normal range (i.e., <7 mg/dL men, <6 mg/dL women) in 51.8%, 75.0%,
and 85.7%, respectively, of the allopurinol alone, benzbromarone
alone, and combination groups (Fig. 4). Perez Ruiz et al additionally
noted in an observational study that the velocity of tophus size reduc-
tion was linearly related to the mean sUA level achieved during ther-
apy [13] (Fig. 1, above).
In a randomized, crossover study, Ohno et al. [57] adjusted the
doses of allopurinol alone or combined allopurinol and benzbromar-
one to achieve a stable low sUA in patients with gout and either nor-
mal renal function or moderate renal dysfunction (n = 45). The
authors observed that combination treatment allowed a lower dose
of allopurinol to be used relative to monotherapy. The importance of
adequate dosing of allopurinol and benzbromarone was shown in a
prospective study of patients with hyperuricemia, where combined
low-dose allopurinol (100 mg) and low-dose benzbromarone (20 mg)
was less effective than standard-dose allopurinol monotherapy for
sUA lowering [58].
Mu€ ller et al observed in a crossover study that benzbromarone
had a pharmacokinetic interaction with allopurinol in patients with
gout (n = 14), resulting in substantially lower plasma steady-state
concentrations of the active allopurinol metabolite, oxypurinol [59].
Similar effects on oxypurinol concentration are reported for other uri-
cosurics (described below). Despite this effect, Mu€ ller et al. reported
that combined benzbromarone and allopurinol was superior to allo-
purinol alone in lowering sUA.
Safety data are not reported in the studies of combined benzbro-
marone allopurinol, with the exception of Ohno et al. [57], who
observed that two patients in the allopurinol group and one patient
in the combined low-dose group showed a slight increase in serum
alanine aminotransferase and serum aspartate aminotransferase.
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Fig. 4. sUA after treatment with allopurinol (A), benzbromarone (B), or both drugs
(A + B). *p < 0.01, A vs B or vs A + B (From Azevedo et al with permission [54]).
Benzbromarone febuxostat
A single paper reports the combination of benzbromarone with
febuxostat, described in hypertensive patients with hyperuricemia
[60]. In this small (20 patients) randomized crossover study, com-
bined low-dose febuxostat (20 mg/day) and low-dose benzbromar-
one (25 mg/day) for 3 months produced significantly greater sUA
lowering than febuxostat alone (40 mg/day) or benzbromarone
alone (50 mg/day) at double doses (¡3.2 § 1.6, ¡2.6 § 1.8, and
¡2.6 § 1.8 mg/dL, respectively; p < 0.01, combination versus both
monotherapies). Excretion of uric acid was increased by benzbro-
marone, but not by febuxostat or combined febuxostat and benz-
bromarone (0.11 § 0.14, ¡0.14 § 0.12, and ¡0.03 § 0.20 mg/kg/h,
respectively; p < 0.01, benzbromarone versus combination and
febuxostat monotherapy).
The authors observed that: “No adverse reactions were noted.”
Although no safety signals were observed, limitations of the study
include low doses of both compounds and a short follow-up for safety
assessments.
Probenecid XOI combination therapy
Probenecid allopurinol
€ and Gutman reported the sUA-lowering effects of allo-
In 1964, Yu
purinol alone and allopurinol combined with uricosuric probenecid
or sulfinpyrazone in an open-label study of 41 patients with gout
not achieving adequate sUA lowering on a uricosuric alone [49]. Allo-
purinol alone at 200 mg or 300 mg, rising to 400 600 mg/day based
on sUA response, was effective in reducing sUA < 7.0 mg/dL in the
majority of patients, while addition of a probenecid or sulfinpyrazone
provided further sUA-lowering (from a mean of 7.1 to 6.1 mg/dL) and
an increased tophus-resolving effect.
In a retrospective, observational study, patients (n = 57) showing
intolerance or lack of efficacy to allopurinol were treated with probene-
cid alone (mean 1.29 § 0.68 g/day) or probenecid (mean 0.99 § 0.44 g/
day) combined with allopurinol (maximum 600 mg/day) [61]. Both
approaches showed only moderate efficacy, with target sUA (<6.0 mg/
dL) achieved in 10/30 (33%) and 10/27 (37%) of respective groups.
Patients with an eGFR < 50 mL/min/1.73 m2 showed similar response
rates to the overall study population. Baseline sUA, but not probenecid
dose or eGFR (<50 versus 50 mL/min/1.73 m2), predicted the likeli-
hood of patients achieving the target sUA.
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Two prospective studies, in healthy subjects and patients with
gout, assessed the sUA-lowering effect of probenecid combined with
allopurinol versus allopurinol alone [62,63]. In the healthy subject
study (n = 12), combining probenecid (1000 mg) and allopurinol
(300 mg) for 7 days provided greater sUA lowering (to 1.5 § 0.3 mg/dL)
than allopurinol alone at the same dose (2.7 § 0.8 mg/dL). For patients
with gout (n = 20), allopurinol at a fixed dose (range: 100 400 mg/day)
combined with probenecid in increasing doses to achieve sUA target
(500 mg/day in most patients) produced a 25% decrease in sUA rela-
tive to allopurinol alone at the same dose (p < 0.001). In both stud-
ies, the greater sUA lowering attained by combination treatment
occurred despite a reduction in plasma oxypurinol concentrations
(26% in the gout patient study) that was related to increased oxypur-
inol renal clearance. Combined probenecid and allopurinol provided
sUA lowering in patients with renal impairment (estimated creati-
nine clearance <50 mL/min), but at a diminished magnitude com-
pared to patients with normal renal function. The addition of
probenecid to allopurinol increased renal clearance of uric acid by
62%. Fractional renal clearances of uric acid and oxypurinol were
correlated (r2 = 0.52; p < 0.001), consistent with URAT1 being the
major transporter for both.
Reinders et al. [64] investigated the sUA-lowering effect of allopu-
rinol (200 300 mg/day) in an open-label study of 51 patients who
had been treated with benzbromarone (100 200 mg/day) prior to its
discontinuation. Only 25% of patients achieved target sUA (<5.0 mg/
dL) on allopurinol significantly fewer than on benzbromarone
(92%) and consistent with earlier comparative studies. Patients not
achieving target sUA on allopurinol alone were additionally treated
with probenecid (1000 mg/day), which increased the proportion
reaching sUA target to 86%. It was concluded that combined probene-
cid and allopurinol was an effective treatment strategy at the doses
studied, equivalent to benzbromarone alone.
With respect to safety parameters, Yu € and Gutman [49] and
Stocker et al [62,63] observed that no drug reactions occurred for
combination or single treatments. Pui et al. [61] recorded adverse
events (AEs) in 10 (18%) patients treated with probenecid, most com-
monly gastrointestinal (n = 3 patients), but did not compare AE rates
for probenecid alone versus combined probenecid and allopurinol.
Probenecid febuxostat
A case report describes a 33-year-old male with poorly controlled
tophaceous gout and chronic kidney disease (CKD) with estimated
GFR of 37 cc/min [65]. Despite maximal dosing of febuxostat (80 mg
twice daily), sUA was 11 mg/dL. Following addition of probenecid
(titrated to 500 mg twice daily) to the febuxostat regimen, sUA
decreased to less than 6 mg/dL after 4 months of combination treat-
ment. The authors conclude that this case illustrates the synergistic
effect of probenecid added to maximal XOI therapy for patients with
refractory hyperuricemia with CKD stage IIIb.
Sulfinpyrazone XOI combination therapy
Sulfinpyrazone allopurinol
Two 1966-dated papers investigated combined sulfinpyrazone
and allopurinol in patients with gout. Allopurinol was described by
Kuzell et al. [48] as a novel approach to gout that could be added to a
uricosuric to promote more rapid resolution of tophi. In this prospec-
tive study, allopurinol (100 mg to 600 mg) combined with sulfinpyra-
zone (100 mg to 1000 mg) in 48 selected patients previously treated
with a uricosuric alone (sulfinpyrazone, probenecid, phenylbutazone,
or oxyphenbutazone) led to greater sUA lowering and increased the
velocity of tophus reduction.
A series of case studies describing patients with extensive topha-
ceous gout reported that allopurinol alone (up to 800 mg) decreased
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sUA in all eight patients (from a mean of 8.6 mg/dL to 6.0 mg/dL),
while the addition of sulfinpyrazone (400 mg) to allopurinol pro-
duced additional sUA lowering in all patients (to a mean of 4.7 mg/
dL) [47]. Consistent with the known mechanisms of action of allopuri-
nol and sulfinpyrazone, urinary uric acid excretion decreased in all
patients treated with allopurinol alone and increased with the addi-
tion of sulfinpyrazone.
Goldfarb and Smyth [47] did not report safety data, while Kuzell et
al. [48] described AEs for allopurinol without distinguishing single
from combination treatment.
Sulfinpyrazone febuxostat
No published studies were identified.
Lesinurad XOI combination therapy
Lesinurad allopurinol
The phase II and III studies of lesinurad in combination with XOIs
(allopurinol and febuxostat) are notable for being well-designed
studies that included large patient numbers and with extensive eval-
uations of both efficacy and safety data; they represent the only phase
III program of combination therapy published to date. It should be
noted that lesinurad monotherapy, while providing sUA lowering in
clinical studies, was associated with an increased rate of renal compli-
cations, and lesinurad should not be prescribed in the absence of con-
comitant XOI [66].
A 4-week, double-blind, phase II trial randomized 208 patients
with gout and an inadequate response to allopurinol alone (i.e.,
sUA  6 mg/dL) to receive lesinurad (200 mg, 400 mg, or 600 mg/day)
or placebo in combination with allopurinol continued at the pre-
study dose (200 600 mg/day) [36]. By 4 weeks, there was a signifi-
cant reduction from baseline in mean sUA and a significant increase
in the proportion of patients achieving sUA < 6 mg/dL in each group
receiving allopurinol and lesinurad combination therapy compared
with the group receiving allopurinol and placebo (p < 0.0001, each
comparison) (Fig. 5). Combined allopurinol and lesinurad were well
tolerated, with adverse event rates generally similar to those with
allopurinol alone. Incidences of serum creatinine (sCr) elevation
(1.5 £ baseline) occurred at higher lesinurad dose levels (0%, 12.8%,
19.7%, versus 2.8%, respectively for lesinurad 200 mg, 400 mg, and
600 mg in combination with allopurinol versus allopurinol alone).
Fig. 5. Proportion of patients achieving sUA < 6 mg/dL at 4 weeks in the ITT population
with non-responder imputation analysis *p < 0.0001 for lesinurad plus allopurinol vs
placebo plus allopurinol (From Perez-Ruiz et al with permission [36]).
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The CLEAR studies (Combining Lesinurad with Allopurinol Stan-
dard of Care in Inadequate Responders) were two replicate,
12-month, placebo-controlled, double-blind, phase III studies of lesi-
nurad (200 mg or 400 mg/day) in combination with allopurinol in
patients who had an inadequate urate-lowering response to standard
of care allopurinol. Patients were required to receive a stable dose of
allopurinol of at least 300 mg per day (200 mg per day in patients
with moderate renal impairment) for at least 8 weeks prior to a
28 day screening period. They also had to have an sUA greater than
6.5 mg/dL at the screening visit and sUA greater than 6.0 mg/dL at the
day-7 visit. Once enrolled in the study, the allopurinol dose was not
changed [34,38]. In both studies (CLEAR 1, n = 610, CLEAR 2, n = 603
patients), lesinurad combined with allopurinol approximately dou-
bled the proportion of patients meeting sUA target (<6 mg/dL) at
month 6 compared with allopurinol combined with placebo (CLEAR
1: 54.2% and 59.2%, lesinurad 200 mg and 400 mg groups, respec-
tively, versus 27.9%, allopurinol alone; p < 0.0001; CLEAR 2: 55.4%
and 66.5%, lesinurad 200 mg and 400 mg groups, respectively, versus
23.3%, allopurinol alone; p < 0.0001) (Figs. 6 and 7). Other efficacy
measures including the proportion of patients meeting sUA targets
<5 mg/dL and <4 mg/dL and the degree of sUA lowering at each
monthly visit were also in favor of combined lesinurad and allopu-
rinol treatment versus allopurinol alone (Figs. 6 and 7). There were
no significant differences between the arms for other secondary end-
point such as the reduction in gout flare rate or the proportion of
patients with complete resolution of tophi, which were at low rates
at baseline and through the study.
The safety profile of lesinurad at the 200 mg dose was comparable
to allopurinol alone, except for higher incidences of serum creatinine
elevation. Thus, overall AE rates in patients in the lesinurad
200 mg + allopurinol, lesinurad 400 mg + allopurinol, and allopuri-
nol + placebo groups were: CLEAR 1 73.1%, 77.6%, and 68.7%; CLEAR
2 74.5%, 80.5%, and 70.9%, respectively. Rates of renal-related AEs
were: CLEAR 1 4.0%, 10.0%, and 3.5%; CLEAR 2 5.9%, 15.0%, and
4.9%, respectively. Treatment with lesinurad in combination with
allopurinol was associated with increased rates of serum creatinine
elevation that were greater for the 400 mg than 200 mg dose (sCr ele-
vation 1.5 £ baseline in lesinurad 200 mg + allopurinol, lesinurad
400 mg + allopurinol, and allopurinol + placebo groups: CLEAR 1
6.0%, 15.9%, and 1.0% patients; CLEAR 2 5.9%, 15.0%, and 3.4%
patients, respectively); most cases of elevation were reversible and
had resolved by the end of the study. The mechanism of sCr elevation
is believed to be via increased excretion of urinary uric acid, which
has the potential to induce uric acid microcrystallization in the renal
tubules that could manifest clinically as transient and reversible ele-
vation in sCr. Based on the incremental efficacy benefit and AE profile
of lesinurad 400 mg in the phase III trials, approval was sought for the
200 mg but not 400 mg dose in combination with an XOI.
A potential concern with uricosurics is the risk of developing kid-
ney stones, which is related to increased urinary uric acid excretion
and microcrystallization in the renal tubules. In the 12-month phase
III studies of lesinurad combined with allopurinol (CLEAR 1, CLEAR 2),
few kidneys stones developed and rates did not differ between the
allopurinol-alone versus combination treatment groups. It has been
suggested that the lack of increase in kidney stones during lesinurad
therapy may be because the concomitant XOI decreases the amount
of uric acid excreted by the kidneys, through reducing uric acid pro-
duction [67].
Lesinurad febuxostat
A phase IB, open-label study assessed the sUA-lowering effects of
febuxostat alone (40 or 80 mg/day, days 1 21) and added lesinurad
(400 mg/day, days 8 14; 600 mg/day, days 15 21) in 20 patients
with gout [68]. Target sUA < 6 mg/dL was attained by 67% and 56% of
patients treated respectively with febuxostat 40 or 80 mg alone,
 ARTICLE IN PRESS
6 F. Perez-Ruiz and N. Dalbeth / Seminars in Arthritis and Rheumatism 00 (2018) 1 11

Fig. 6. Proportion of subjects achieving sUA targets of < 6.0 mg/dL, < 5.0 mg/dL, and < 4.0 mg/dL by months 6 and 12 (ITT population). *p < 0.0001; **p < 0.01 (From Saag et al with
permission [38]).

which increased to 100% of patients treated with lesinurad 400 or
600 mg in combination with febuxostat. sUA lowering was signifi-
cantly greater for both lesinurad combination therapy groups versus
febuxostat alone (see Fig. 8). Renal clearance of uric acid was
decreased by febuxostat alone and increased by combination therapy
relative to baseline, consistent with the renal mechanism of action of
lesinurad.
The phase III studies of lesinurad include the 12-month, placebo-
controlled, double-blind CRYSTAL study (Combination Treatment
Study in Subjects with Tophaceous Gout with Lesinurad and Febuxo-
stat), which investigated lesinurad (200 or 400 mg/day) in combina-
tion with febuxostat (80 mg/day) versus febuxostat combined with
placebo in 324 patients with tophaceous gout [35]. Target
sUA < 5 mg/dL at 6 months was attained by 56.6% and 76.1% of
patients in the combined lesinurad 200 mg and 400 mg with febuxo-
stat groups, respectively, versus 46.8% for combined febuxostat and
placebo (p = 0.13 and p < 0.0001, lesinurad groups versus febuxostat
alone) (Fig. 8). At every other time point, more patients achieved the
sUA target in the combined lesinurad 200 mg and febuxostat than
combined febuxostat and placebo group (p-values  0.028) (month
12 data in Fig. 8). Mean of gout flare rates from month 6 to month 12
was reduced in the combined lesinurad 400 mg and febuxostat versus
combined febuxostat and placebo group (p = 0.04), while there were
no significant differences between the arms for the proportion of
patients with complete resolution of target tophi. At month 12, the
lesinurad 200 mg plus febuxostat and lesinurad 400 mg plus febuxo-
stat groups had a significantly higher mean percent reduction from
baseline in the sum of areas of all target tophi when compared with
the combined febuxostat with placebo group.
In the CRYSTAL study, AEs occurred in the lesinurad
200 mg + febuxostat, lesinurad 400 mg + febuxostat, and febuxo-
stat + placebo groups in 82.1%, 82.6%, and 72.5% patients, respectively,
with renal-related AEs in 8.5%, 10.1%, and 5.5%. sCr eleva-
tion  1.5 £ baseline occurred in 4.7%, 10.1%, and 2.8% patients in the
lesinurad 200 mg + febuxostat, lesinurad 400 mg + febuxostat, and
febuxostat + placebo groups. All cases of sCr elevation resolved by the
final study assessment, with the exception of one case each in the
lesinurad 200 mg + febuxostat and lesinurad 400 mg + febuxostat
groups. As in phase III studies of lesinurad combined with allopurinol
(CLEAR 1, CLEAR 2), the CRYSTAL study reported low rates of kidneys
stones that were similar between the febuxostat-alone and combina-
tion treatment groups.
Lesinurad allopurinol or febuxostat (open label extension studies)
Long-term studies demonstrate the importance of maintaining
low sUA levels in order to improve gout symptoms. An extension
study of patients in CLEAR 1 and CLEAR 2 combined (n = 716) mea-
sured sUA levels over an additional 12 months of combined lesinurad
and allopurinol treatment, and reported that target sUA levels were

Fig. 7. Proportion of subjects achieving sUA targets of < 6.0 mg/dL, < 5.0 mg/dL, and < 4.0 mg/dL by months 6 and 12 (intent-to-treat population). *p < 0.0001 (From Bardin et al
with permission [34]).

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 ARTICLE IN PRESS
F. Perez-Ruiz and N. Dalbeth / Seminars in Arthritis and Rheumatism 00 (2018) 1 11 7

Fig. 8. Proportion of subjects achieving sUA targets of <6.0 mg/dL, <5.0 mg/dL,<4.0 mg/dL, and <3.0 mg/dL by month 6 and month 12 (intent-to-treat population). *p < 0.001;
#
p < 0.05 (From Dalbeth et al with permission [35]).

maintained by consistent proportions of patients (»65% and »80%
patients in lesinurad 200 mg and 400 mg combination groups, respec-
tively) [37](Fig. 9). Patients who switched from combined allopurinol
and placebo to combined lesinurad and allopurinol treatment at the
end of the double-blind studies gained similar rates of target sUA lev-
els during the extension study (»70%).
Adverse event rates during the extension study in patients who
switched from combined allopurinol and placebo to combined lesi-
nurad 200 mg or 400 mg with allopurinol (76.2% and 77.0% of
patients, respectively) were generally similar to those in patients
who continued lesinurad 200 mg or 400 mg in combination with allo-
purinol (77.9% and 81%, respectively) [37]. Renal-related AEs were
15.6% and 21.3%, respectively, in patients who switched from com-
bined allopurinol and placebo to combined lesinurad 200 mg or
400 mg with allopurinol, and were 15.4% and 23.7% in patients who
continued lesinurad 200 mg or 400 mg in combination with allopuri-
nol. Rates of sCr elevation (1.5 £ baseline) during the extension
were lower for lesinurad 200 mg (13.9% and 13.8%, respectively in
patients who switched to or continued lesinurad) than for lesinurad
400 mg (32.0% and 26.7%, respectively) in combination with allopuri-
nol.
Previous studies in gout have reported that ULT must be main-
tained for an excess of 1 year to adequately lower gout flare rates and
induce tophus resolution, which is expected to be the time to lower
body urate stores [11,13,69]. An analysis of patients in the CLEAR 1,
CLEAR 2, and CRYSTAL extension studies combined (n = 535) included
assessments of tophus resolution and rates of gout flares, and showed
that efficacy, i.e., no attenuation of serum urate effect, continued
reduction in gout flares was maintained over 12 months, while there
were no new safety signals [70].
Verinurad XOI combination therapy
Phase I and II studies in patients with gout have compared veri-
nurad combination treatments with XOI alone or verinurad alone for
sUA lowering and uric acid excretion.
Verinurad allopurinol
Adult men with gout (n = 12) were randomized in a phase I study
to receive daily doses of allopurinol (300 mg) alone, verinurad
(10 mg) alone, and combined verinurad (10 mg) and allopurinol
(300 mg) in sequence [71]. The maximum decrease in sUA was
greater with combined verinurad and allopurinol (65.2%) than with
verinurad (50.5%) or allopurinol (43.0%) alone (Fig. 10). Relative to
baseline, the maximum rate of uric acid excreted in urine was
decreased 46% by allopurinol, increased 56% by verinurad, and
unchanged by combined verinurad and allopurinol [71].

Fig. 9. Proportion of patients with sUA < 6.0 mg/dL during the CLEAR core and extension studies (ITT population observed cases). 200CROSS, 400CROSS: patients switched to lesi-
nurad + allopurinol during extension study; 200CROSS, 400CROSS: patients continued on lesinurad + allopurinol doses (From Saag et al with permission [37]).

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 ARTICLE IN PRESS
8 F. Perez-Ruiz and N. Dalbeth / Seminars in Arthritis and Rheumatism 00 (2018) 1 11
Fig. 10. Mean (SE) percent change in sUA at steady state following verinurad 10 mg, allopurinol 300 mg, or in combination (From Kankam et al. with permission [71]).
Verinurad was well tolerated [71]. One treatment-emergent AE
(TEAE; petechiae) was considered by the investigator to be possibly
related to both verinurad and allopurinol. Two subjects experienced
an increase in sCr, but neither experienced an sCr value 1.5 £ base-
line.
A phase IIa study in adults with gout (n = 41) investigated the
pharmacodynamics, pharmacokinetics, and safety of verinurad (dose
range: 2.5 mg 20 mg/day) combined with allopurinol (300 mg/day),
using allopurinol alone (300 mg or 600 mg/day) as comparator [40].
Verinurad and allopurinol combination treatment produced dose-
dependent decreases in sUA (maximum decrease range: 47% 74%)
that were greater than achieved with allopurinol (300 mg/day) alone
40%). Verinurad 5 mg in combination with allopurinol 300 mg addi-
tionally lowered sUA more than allopurinol 600 mg alone (54%).
Adverse events were reported in 12 (29.3%) patients, most fre-
quently upper respiratory tract infection (n = 4) and headache (n = 3).
No AEs were considered related to verinurad or allopurinol. No clini-
cally meaningful changes in laboratory values or vital signs were
observed, including no cases of sCr elevation 1.5 £ baseline.
Verinurad febuxostat
A phase IIa, open-label study in 64 adults with gout investigated
the pharmacodynamics, pharmacokinetics, and safety of verinurad
(dose range: 2.5 20 mg/day) in combination with febuxostat (40 or
80 mg), versus febuxostat alone at the same doses [39]. The maxi-
mum percent decrease in sUA was dose-dependent, ranging from
52% to 77% for verinurad 2.5 to 20 mg combined with febuxostat
40 mg (versus 42% for febuxostat 40 mg alone), and from 62% to 82%
for verinurad 2.5 to 15 mg combined with febuxostat 80 mg (versus
55% for febuxostat 80 mg alone). Combinations of verinurad 5 mg
with febuxostat 40 mg had a greater sUA-lowering effect than
febuxostat 80 mg alone. The urinary uric acid excretion rate was
reduced below baseline by febuxostat alone and was comparable to
baseline for verinurad combined with febuxostat.
Adverse event rates were 4.9% during febuxostat 40 mg, 15.7%
during febuxostat 80 mg, and 21.0% during combined veri-
nurad + febuxostat. The most frequent TEAE possibly related to study
medication was pain in extremity, in two patients receiving veri-
nurad. No clinically meaningful changes in laboratory values or vital
signs were noted.
A phase IIa study in Japanese subjects with gout or asymptomatic
hyperuricemia (n = 72) assessed sUA lowering with daily treatment
by verinurad (2.5 10 mg) in combination with febuxostat (10, 20,
40 mg), verinurad alone (2.5 15 mg), febuxostat alone (10, 20,
40 mg), or benzbromarone alone (50 mg) [41]. Combined verinurad
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with febuxostat decreased sUA in a dose-dependent manner, provid-
ing greater sUA lowering than febuxostat alone at the same doses.
Combined verinurad 5 mg and febuxostat 20 mg had a comparable
sUA-lowering effect to benzbromarone 50 mg.
Five subjects reported six TEAEs during treatment or follow-up,
including one subject with a TEAE (diarrhea) considered causally
related to both verinurad and febuxostat. Two subjects treated
with verinurad 2.5 mg or verinurad 15 mg alone showed an sCr ele-
vation 1.5 £ baseline.
Arhalofenate febuxostat combination therapy
A phase II study investigated the sUA-lowering effects of arha-
lofenate alone (600 or 800 mg daily), febuxostat alone (40 or 80 mg),
and combined arhalofenate and febuxostat in 32 patients with gout
[43]. Greatest sUA lowering (63%) was provided by the highest doses
of arhalofenate (800 mg) and febuxostat (80 mg) in combination,
which was significantly greater than for arhalofenate or febuxostat
alone (p < 0.0001) (Fig. 11). Mean sUA decreases from baseline were
54% and 55%, respectively, for combined arhalofenate (600 mg) with
febuxostat (80 mg) and for combined arhalofenate (800 mg) with
febuxostat (40 mg). Arhalofenate is under investigation for treatment
of gout via both uricosuric and anti-flare activities, although flare
data were not reported in the current short study.
TEAEs were reported in 71.9% patients overall, but were not
reported for individual treatment groups. One subject had a TEAE of
elevated liver transaminases that was possibly related to febuxostat
and possibly related to arhalofenate and colchicine. No cases of sCr
elevation 1.5 were recorded.
Discussion: benefits of combination therapy
The clinical studies in this review were performed from the 1960s
to the present and utilized a range of designs, durations, and dose
regimens. Among approved treatments, the older uricosurics were
investigated in open-label uncontrolled studies, while lesinurad alone
has been investigated in randomized, controlled phase III studies in
combination with an XOI. Despite the limitations of some of the data,
there is consistency in the observation that combined treatment with
a uricosuric and an XOI provides substantially greater sUA lowering
than achieved by either monotherapy and can be a useful approach
when the target therapeutic sUA is not reached with monotherapy
alone. Greater sUA lowering translated to greater gout symptom con-
trol, including improved tophus resolution. These consistent study
data, therefore, show that combination therapy offers an effective
 ARTICLE IN PRESS
F. Perez-Ruiz and N. Dalbeth / Seminars in Arthritis and Rheumatism 00 (2018) 1 11
Fig. 11. Mean percent reduction from baseline in sUA from Day 1 throughout the
study for pharmacokinetic (PK, open circles) and non-PK (closed circles) cohorts. Mean
baseline sUA was 9.2 mg/dL and 9.4 mg/dL for PK and non-PK cohorts, respectively.
FBX40, febuxostat 40 mg; FBX80, febuxostat 80 mg. (From Steinberg et al with permis-
sion) [43].
option in managing patients with gout who do not achieve target sUA
with XOI monotherapy or are intolerant of XOIs at higher dosing.
Patients included in the clinical studies were broadly representa-
tive of those encountered in clinical practice, including patients with
difficult-to-treat disease due to severe or complex symptoms, a his-
tory of non-response to ULT, and comorbidities (most commonly
renal impairment). In this context, combination therapy represents
an important resource with expectations of successful sUA lowering
in a substantial proportion of patients who are not adequately con-
trolled with monotherapy. Importantly, there have been no studies
that directly address whether addition of a uricosuric agent to an XOI
is a more effective and safer approach than dose escalation of a xan-
thine oxidase agent as monotherapy.
A comparison of the sUA-lowering potency of the individual com-
ponents of combination therapy was not the aim of this review. How-
ever, those studies that compared monotherapies in this review
suggest broadly similar sUA-lowering efficacy between the XOI and
uricosuric classes within clinically relevant dose ranges. Pharmacoki-
netic data from studies show there is no drug drug interaction
between XOIs and uricosurics, besides a reduction in levels of oxypur-
inol (the major active metabolite of allopurinol and a purine ana-
logue) that is explained by URAT1 being the major transporter for
both urate and oxypurinol, contrary to febuxostat, a non-purine com-
pound.
In clinical practice, a key limitation of combination therapy may
be the burden of additional medications. The availability of a fixed-
dose combination formulation of combination therapy may offer ben-
efits over individually dosed combinations in terms of improved
patient adherence and physician acceptability. This is the experience
in other specialties that utilize fixed-dose combination formulations
in long-term management [72 79]. A further potential limitation of
combination therapy is the possibility of additional drug interactions
compared with monotherapies alone. The distinct mechanisms of
action of uricosurics and XOIs indicate that there little potential for
drug-interaction effects between these agents or likelihood of addi-
tional interactions with other drugs.
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9
Studies describing older agents such as probenecid, benzbromar-
one, and sulfinpyrazone do not specifically capture safety data,
especially in relation to long-term use, and are in contrast to the
well-controlled investigations of more recently developed uricosu-
rics, subject to standardized clinical trial procedures. Lesinurad is a
uricosuric approved at a 200 mg daily dose in combination with an
XOI, which in phase III studies demonstrated AE rates similar to the
comparator XOI alone, other than an increased incidence of renal
effects, i.e., serum creatinine elevations. As noted earlier, combining
an XOI with a uricosuric reduces urinary uric acid excretion and
hence the propensity to renal adverse effects relative to uricosuric
therapy alone. It is recommended to monitor renal function at initia-
tion and during combined lesinurad and XOI therapy, particularly in
patients with estimated creatinine clearance below 60 mL/min, and
to evaluate for signs and symptoms of acute uric acid nephropathy.
Monitoring of sUA is additionally encouraged during therapy, to
ensure that patients meet and sustain the target sUA levels. Uricosu-
ric therapy is contraindicated in patients with severe renal
impairment(CrCl < 30 mL/min), end-stage renal disease, kidney
transplant recipients, or patients on dialysis. Maintaining adequate
fluid intake is recommended during uricosuric treatment to reduce
the risk of nephrolithiasis.
In conclusion, combination therapy with a uricosuric and XOI
offers additional lowering of sUA levels that is of benefit for achieving
therapeutic targets in patients with gout who do not achieve their
target sUA on monotherapy alone.
Funding
Editorial support for this manuscript was provided by Bill Wolvey
of PAREXEL, which was funded by Ironwood Pharmaceuticals.
Declaration of interest
Dr F Perez-Ruiz: Advisory fees from AstraZeneca, Gru€ nenthal, and
Menarini. Speaker fees from Gru € nenthal and Spanish Foundation for
Rheumatology. Investigation grants from Spanish Foundation for
Rheumatology and Cruces Rheumatology Association.
Dr N Dalbeth: Grant funding, consultancy, or speaker fees from
Takeda, Ardea Biosciences, AstraZeneca, Kowa, and Horizon.
Supplementary materials
Supplementary material associated with this article can be found,
in the online version, at doi: 10.1016/j.semarthrit.2018.06.004.
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