Joint Bone Spine 84 (2017) 541–546

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Severe gout: Strategies and innovations for effective management

Eliseo Pascual a,b,∗ , Mariano Andrés a,b , Janitzia Vázquez-Mellado c , Nicola Dalbeth d
a
Sección de Reumatología, Hospital General Universitario de Alicante, Av. Pintor Baeza 12, 03010 Alicante, Spain
b
Departamento de Medicina Clínica (Reumatología), Universidad Miguel Hernández, Carretera Nacional 332 S/N, 03550, San Juan de Alicante, 03010
Alicante, Spain
c
Servicio de Reumatología, Hospital General de México, Dr. Balmis 148, Cuauhtémoc, Doctores, 06726 Ciudad de México, D.F., Mexico
d
Department of Rheumatology, Auckland District Health Board and Department of Medicine, University of Auckland, Auckland 1010, New Zealand

a r t i c l e i n f o a b s t r a c t

Article history: Severe gout is characterised by frequent polyarticular flares, numerous tophi, joint damage, and muscu-
Accepted 10 October 2016 loskeletal disability. This is a preventable condition and in many cases, represents a disease that has
Available online 5 December 2016 been insufficiently managed for years. Standard management recommendations may be insufficient
for patients with severe gout; these patients frequently require intensive individualised pharmacolog-
Keywords: ical management with combinations of urate-lowering therapy and anti-inflammatory agents. In this
Severe gout article, we aim to integrate recent therapeutic advances to provide a practical framework for optimal
Refractory
management of severe gout.
Management
Colchicine
© 2017 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
Allopurinol
Febuxostat
Tophus

1. Introduction
In clinical practice, severe gout presents as frequent polyartic-
ular flares, extensive tophaceous deposits, joint damage, and
musculoskeletal disability. Although there is no widely accepted
definition for severe gout, the recent American College of Rheu-
matology (ACR) Gout Management Guidelines have defined as
severe chronic tophaceous gouty arthropathy those cases with
“>4 tophi, or at least one unstable, complicated or severe tophus”
[1]. In the clinical trials of pegloticase, for which a definition to
select patients was necessary, gout was considered as ‘refrac-
tory’ if the following were present: “a baseline serum urate (SUA)
≥8.0 mg/dl and 3 or more self-reported gout flares in the pre-
vious 18 months, 1 or more tophi, or gouty arthropathy.” [2]. A
threshold of 5 tophi has also been used in other studies to define
gout as severe [3]. None of these definitions is evidence based;
since severity and its consequent management difficulties occur
as a continuum and may be influenced by other circumstances,
these definitions insufficiently cover those scenarios where man-
agement difficulties may occur. For this article, we consider
severe gout to be characterised by a large burden of accumulated
monosodium urate (MSU) crystals with associated joint damage
∗ Corresponding author at: Sección de Reumatología, Hospital General Universi-
tario de Alicante, Pintor Baeza 12, 03010 Alicante, Spain.
E-mail address: pascual eli@gva.es (E. Pascual).
(Fig. 1), and/or frequent or even continuous flaring, oligo or pol-
yarticular flares, associated comorbidities (such as chronic kidney
disease (CKD), heart failure or metabolic syndrome), and/or drug
intolerance.
In the last decade, there have been major advances in the
understanding and management of gout, with approval of new
therapeutic agents, publication of treatment guidelines, and iden-
tification of therapeutic SUA targets for effective management of
gout. In this article, we aim to integrate these advances to provide
a practical framework for optimal management of severe gout. Key
management points are summarised in Table 1 and a decision tree
is shown in Fig. 2. Local drug availability and approvals should be
considered by individual readers.
The key concept for effective management for all patients with
gout is that this is a reversible crystal deposition disease, so the
central aim of treatment is the reduction and final elimination
of monosodium urate (MSU) crystals by normalising SUA levels
[2,4–6]. Additionally, flares occurring during initiation or during
of urate-lowering therapy should be avoided, and if flares do occur,
they should be rapidly and effectively treated. Attention must be
paid to comorbidities that may result from gout or complicate its
management. Finally, patients must be informed of the character-
istics of the disease, its treatment, and the role of the different
drugs required. These five components of gout management may
pose difficulties in those patients with severe disease, especially
when the patient considered as a failure previous attempts of treat-
ment [6].

http://dx.doi.org/10.1016/j.jbspin.2016.10.004
1297-319X/© 2017 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
542 E. Pascual et al. / Joint Bone Spine 84 (2017) 541–546
Fig. 1. Example of severe gout. Numerous large tophi with associated joint defor-
mity in the hands of a young patient with severe gout.
2. Reduction of SUA levels
In a prospective study of joint aspirations in patients with gout
on urate-lowering therapy, the recommended therapeutic SUA tar-
get of <6 mg/dl [to convert into mol/l, multiply 59.48] resulted
Fig. 2. Decision tree for severe gout assessment and management. ALLO: allopurinol; CKD: chronic kidney disease; FBX: febuxostat; GCC: glucocorticoids; IL-1: interleukin 1;
IA: intra-articular; IM: intramuscular; NSAIDs: non-steroidal anti-inflammatory agents; SUA: serum uric acid; ULT: urate-lowering therapy. † Other features may also indicate
severe gout.
Table 1
Key points in the management of severe gout.
Patients with severe gout often have insufficient response to standard
management approaches and require intensive individualised
pharmacological treatment
In patients with severe gout, serum urate levels well below 5 mg/dl
(300 ␮mol/l) are required to enhance crystal dissolution, using
urate-lowering drugs at maximal doses or in combination
Flexible prophylaxis is needed as flares often occur after serum urate
reduction in patients with severe gout
Comorbidities such cardiovascular or kidney disease are common in patients
with severe gout and often determine therapeutic approaches
Severe gout is often the result of neglected disease; effective urate-lowering
therapy should be established in people with gout well before the
development of extensive MSU crystal deposition, tophi, and joint damage
in crystal dissolution in 16 out of 19 patients sampled [7]. Val-
ues below 5 mg/dl are now recommended for severe gout by the
European League Against Rheumatism [5], the British Society for
Rheumatology [8] and the ACR [1]. Lower SUA values lead to faster
diminution of tophus size and earlier disappearance: SUA values
<4 mg/dl result in twice the rate of tophus diameter reduction than
values >5 mg/dl [9]. Profound SUA lowering by pegloticase also
results in fast disappearance of tophi [2]. By setting the SUA tar-
get we are deciding on the time to crystal disappearance. When
the burden of accumulated MSU crystals is very large, SUA targets
 E. Pascual et al. / Joint Bone Spine 84 (2017) 541–546
well below 5 mg/dl are most often required. Due to the scarcity of
literature on the subject, setting a value is, at this point, arbitrary.
Slow dissolution of crystals in patients with severe gout may
lead to the appearance of a disease that is refractory or poorly
responsive to treatment. Although the total duration of very low
levels of serum urate necessary to dissolve large deposits of MSU
crystals is prolonged, the limited available information suggest that
3–5 years may be enough for a majority [10], followed by levels
maintained below 6 mg/dl (and preferably lower during some addi-
tional years in patients with severe gout) to ensure dissolution of
remaining crystal deposits and avoidance of formation of crystals
anew. Crystal deposits inside tendons – like the patella tendon –
may take longer to disappear [11]. The possibility of evaluating
the burden of the remaining crystal deposit using ultrasonogra-
phy or dual energy computed tomography is now an interesting
possibility.
2.1. Allopurinol
In patients with severe gout, urate-lowering strategies require
careful tailoring to the individual patient in order to achieve such
low SUA targets and hasten crystal clearance; this tailored scheme
is able to achieve improved outcomes [12]. Target SUA levels
may be achieved by xanthine oxidase inhibitors (XOI; allopuri-
nol, febuxostat) alone, at the highest approved doses. Allopurinol
remains the only available urate-lowering therapy in a number of
countries, and therefore optimal management of this drug in these
countries is essential. In all patients with gout, a low starting dose of
allopurinol (daily dose of 1.5 mg/unit of estimated glomerular fil-
tration rate) with slow dose up-titration (by 50–100 mg/month)
until the desired therapeutic SUA target is reached has been
suggested [5,6,13] This approach has the dual benefits of (a)
reducing the risk of flares that accompany sudden SUA reduc-
tion, especially frequent in severe gout patients; and (b) potentially
reducing the risk of severe allopurinol-associated side effects. The
maintenance dose of allopurinol must be defined by the target
SUA level. This dosing strategy is particularly relevant in severe
gout, where maximal approved allopurinol doses (800–900 mg/d)
may be needed to achieve the low therapeutic SUA target. In
patients with reduced kidney function, a dose adjustment based
on the creatinine clearance has been recommended [14]. How-
ever, restricting maintenance allopurinol doses according to kidney
function is insufficient to achieve therapeutic SUA targets in most
patients [15], and a gradual dose up-titration above the ‘renally-
adjusted dose’ to achieve the target is often required [12,16,17].
2.2. Febuxostat
Febuxostat is a non-purine selective XOI. The hepatic
metabolism of febuxostat is a major advantage for many
patients with severe gout, as dose adjustment is not required
in those with mild or moderate CKD. Patients with severe CKD
(eGFR < 30 mL/min/1.73 m2 ) were excluded from the febuxostat
phase 3 clinical trials, and caution has been recommended in those
with cardiovascular disease–coronary disease or heart failure [18].
Febuxostat can be a useful alternative urate-lowering drug in those
who are allopurinol intolerant [19], although the risk of skin reac-
tions with febuxostat is not absent [20]. In order to achieve target
SUA for severe gout, the maximum approved doses of febuxostat
(120 mg/day) are often required; in the FACT study, SUA < 5 mg/dl
was achieved in 47% of those receiving 80 mg febuxostat daily and
66% of those on 120 mg febuxostat [21]. Furthermore, SUA < 4 mg/dl
was achieved in 20% of those receiving 80 mg febuxostat daily and
41% of those on 120 mg febuxostat. Thus, some febuxostat-treated
patients may not achieve target SUA values required for treat-
ment of severe gout. The available dosing does not permit small
543
increments in dose escalation, so the probability of flares in severe
gout patients is significant and careful flare prophylaxis should be
considered when commencing febuxostat (see below).
2.3. Uricosurics
Uricosurics act by reducing urate reabsorption at the renal
tubules, so raising its renal clearance. Benzbromarone and
probenecid are still in use but availability is limited in a number
of countries. If XOI monotherapy strategy fails to achieve target
SUA levels, allopurinol in combination with a uricosuric can result
in further important SUA reductions [11,22,23], by diminishing
the amount of urate produced while raising its renal clearance.
This combination has the advantage that the total amount of UA
excreted (and thus the risk of nephrolithiasis) is reduced. Benzbro-
marone requires close liver function test monitoring. The efficacy
of benzbromarone and probenecid is generally limited in patients
with severe CKD, although responses generally occur in those with
moderate CKD [24], and in such patients with severe gout and
limited treatment options, a uricosuric trial is warranted. In the
occasional patient who is intolerant to both XO inhibitors, urico-
suric monotherapy with probenecid or benzbromarone offers an
effective alternative [25]. This is also the case for patients taking
azathioprine (i.e. after solid organ transplantation), in whom XO
inhibitors may increase toxicity. The URAT-1 inhibitor lesinurad
was approved by the US Food and Drug Administration in 2015 for
use in combination with a XOI [26], and other newer uricosurics
are now being developed.
2.4. Uricases
When a rapid and profound reduction of SUA is required for
treatment of severe gout, a course of recombinant uricase (ras-
buricase or pegloticase) will hasten the dissolution of MSU crystals
[3,27]. Rasburicase is approved for prevention of tumour lysis syn-
drome. Although this agent has a short half-life (<24 h), a small
study reported that monthly intravenous infusions reduced tophus
burden in patients with severe gout [26]. Pegloticase is a pegy-
lated form of recombinant uricase approved for use in gout that is
refractory to conventional therapies, with the advantages of longer
duration of action and better tolerance. Fortnightly intravenous
administration of pegloticase leads to profound hypouricaemia in
treatment responders (SUA < 1 mg/dl), which is accompanied by
rapid regression of subcutaneous tophi, and improvement in flare
frequency, joint pain, activity limitation and health related quality
of life [3,28]. Infusion reactions in relation with the development of
immunogenicity may limit the use of pegloticase in some patients.
In these cases, an initial loss of SUA response in comparison to pre-
vious infusions, due to the presence of antibodies, is often seen prior
to the occurrence of infusion reactions. This led the FDA to recom-
mend not using other urate-lowering therapy in combination with
pegloticase [29]. Price and availability are limitations for the use of
these drugs.
2.5. Additional considerations of urate-lowering therapy
Crystal removal eventually leads to the disappearance of the
clinical features of gout, which is why the disease may be con-
sidered as curable. Patients with severe disease can show further
benefits from crystal removal. Decreased kidney function associ-
ated to severe gout may relate to crystal deposits and small tophi
at the renal medulla [30–32], likely producing associated inflam-
mation. Some reports have shown kidney function stabilisation
or improving after urate-lowering treatment [33,34]. Avoidance
or lower intake of NSAIDs may also contribute to this improve-
ment in kidney function. Gout is an independent cardiovascular risk
544 E. Pascual et al. / Joint Bone Spine 84 (2017) 541–546
factor [35,36,37], and persistent subclinical inflammation induced
by MSU crystals has been implicated in cardiovascular disease in
patients with gout [38]. Cardiovascular disease risk appears to be
even higher in patients with severe gout [39,40]; as mentioned,
these patients frequently have a large burden of accumulated
MSU crystal. To date, it is unclear whether urate-lowering ther-
apy reduces the incidence of cardiovascular events. Nevertheless,
this appears plausible and provides further justification for rapid
crystal clearance in patients with severe gout and atherosclerotic
comorbidities [41].
Additional important issues regarding use of urate-lowering
therapy in severe gout are the timing of starting treatment, appro-
priate monitoring techniques, and the duration of very low SUA
levels. Traditionally, initiation of urate-lowering therapy has been
delayed in those with acute flares, due to concerns about the risk
of worsening or prolonging the flare. Patients with severe gout
may have constant or very frequent flares, and this advice can
be a barrier to initiating urate-lowering therapy. Recent clinical
trial data suggest that urate-lowering therapy can be safely ini-
tiated during a flare [42], and this is frequently possible in those
with severe gout if a slow escalation approach is taken. Measure-
ment of SUA levels is the essential monitoring tool for effective
management of severe gout [43]. Kidney function should also be
monitored. Additional tools for clinical monitoring of urate bur-
den include measurement of index tophi using Vernier callipers,
clinical photography or ultrasound [44]. Many patients with severe
gout show restricted joint function due to urate crystal deposits in
joints or tendons [45], which improves substantially after effective
urate-lowering therapy. Therefore, it is worth recording any lim-
itation of joint movement at the initiation of the treatment and
during the follow-up period, although joint limitation improves
after a few months of proper treatment encouraging the patient
to adhere to the treatment. An area of controversy is whether
very low SUA levels (i.e. <3 mg/dl) should be maintained for pro-
longed periods. Although epidemiological observational studies
have suggested that hypouricaemia is associated with development
of neurological disease [46,47], this risk is not currently supported
by urate-lowering therapy clinical trial data. Based on these data,
the 2016 updated EULAR guidelines recommended against main-
taining SUA level to <3 mg/dl “in the long term that is, for several
years” [5].
3. Anti-inflammatory flare prophylaxis
In patients with severe gout, anti-inflammatory prophylaxis at
the time of starting urate-lowering therapy is essential, as rapid
reductions in SUA frequently result in severe flares [20]. Although
six months of prophylaxis is recommended for most patients with
gout [48], longer duration is frequently required for those with
severe gout due to persistent MSU crystal deposition even when
the SUA target has been achieved; it has been reported that sus-
tained treatment with colchicine has beneficial CV effects [49].
Flares result from the presence of urate crystals and may occur
while crystals remain, and patients should be warned that if new
flares occur while on urate-lowering treatment it does not mean
that this treatment is ineffective. In fact, recurrent acute attacks
are not necessarily a sign of ineffective urate-lowering therapy, but
of insufficient prophylaxis.
In most patients with gout, flares can be prevented by gradual
urate-lowering therapy dose escalation and the use of colchicine
0.5–1 mg/d or low dose NSAIDs (less convenient due to kidney and
cardiovascular risk) [50]; the dose of colchicine must be reduced
in those with diminished kidney function. Colchicine is tolerated
by some patients with end stage kidney disease on haemodialysis
[51], although further dose reduction is recommended [52] Careful
monitoring for adverse effects is needed in this group.
Patients with severe gout may be very sensitive to changes
in SUA levels, so that flares occur despite “standard” prophy-
laxis. A flexible prophylaxis scheme is often required, including
combinations of colchicine, NSAIDs and/or low-moderate doses of
prednisone that should be titrated up and down and kept for a
limited period of time, depending on the individual patient. In order
to maintain patient engagement and adherence to urate-lowering
therapy, it is important that all patients with gout have medica-
tions easily available to rapidly treat acute flares if they occur, be
advised that flares occur as consequence of urate-lowering therapy
efficacy, and understand that once SUA levels normalise flares will
gradually subside completely [53].
4. Treatment of flares
Polyarticular flares occur frequently in patients with severe
gout. Urate-lowering therapy should be continued while the
attack is treated. In patients with severe gout, NSAIDs are often
contra-indicated due to comorbid conditions (cardiovascular, kid-
ney), and colchicine monotherapy may be insufficient or poorly
tolerated. Concomitant use of CYP3A4/P-glycoprotein inhibitors
including cyclosporine and calcium channel blockers may fur-
ther complicate colchicine prescribing and increase the risk of
colchicine toxicity [54]. A short course of prednisolone (30–35 mg
daily during 5 days (5)) is particularly useful in this situation
[5,55]. Occasionally patients present with prolonged polyarticular
and systemic inflammation, and in this situation, the pred-
nisone course should be longer and adapted to the subsidence
of the inflammation. Intraarticular corticosteroids are also a good
choice for mono or oligoarticular flares and can be combined
with systemic treatment if necessary. Anakinra, an interleukin-1
inhibitor is effective in those patients in whom standard anti-
inflammatory agents are ineffective or not tolerated [56,57]; a
few daily doses subsides rapidly most attacks. A longer acting
interleukin-1 inhibitor, canakinumab, is now approved by the Euro-
pean Medicines Agency for treatment of gout flares in patients for
whom other anti-inflammatory drugs are ineffective or contra-
indicated [58]. Canakinumab also prevents recurrent flares for
some time after administration [54], a particular advantage for
those with severe gout. Treatment of flares should be accompanied
and followed by colchicine in prophylactic doses to avoid rebound
flares once the flare treatment is over, a common occurrence in
patients with severe gout.
5. Non-pharmacological considerations
Disability resulting from gout can be very severe and inca-
pacitating [59], but is at least partially reversible after proper
pharmacological treatment [2,12]. Footwear and assistive devices
may be helpful to some of these patients [60]. Dietary changes
alone are unlikely to lead to achievement of SUA targets in patients
with severe gout, and should not be considered an alternative to
pharmacological treatment. In the case of accessible tophi causing
complications such as infection, ulceration, severe cosmetic prob-
lems or functional impact, surgical removal can be considered as an
adjunct to intensive urate-lowering therapy [61]. A patient-centred
approach focusing on education about MSU crystal deposition as
the central cause of gout and the need for SUA lowering is essential
for all patients with gout, and particularly those with severe disease
[62].
6. Prevention of severe gout and conclusions
Severe gout is a preventable condition that causes pain, disabil-
ity and poor quality of life. This disease state reflects the advanced
 E. Pascual et al. / Joint Bone Spine 84 (2017) 541–546
continuum of crystal deposition. In most cases, severe gout repre-
sents neglected disease that has been untreated or insufficiently
managed for many years. We appeal to all health professionals to
take gout seriously, and to ensure the early use of effective urate-
lowering therapy well before the development of extensive MSU
crystal deposition, tophi, and joint damage.
Search strategy
A PubMed search under the terms of [severe gout – treatment]
and [tophaceous gout – treatment] from 2000 on has been carried
out. We also manually searched the reference lists of the retrieved
articles in order to increase literature search.
Funding
Nicola Dalbeth is supported by the Health Research Council of
New Zealand (12-111).
Author contributions
All authors contributed to the drafting of the manuscript and
approved the final version.
Disclosure of interest
ND has received consulting, speaker fees or grants from
the following companies: Takeda, Teijin, Menarini, Ardea, Pfizer,
AstraZeneca, Cymabay, Fonterra, Crealta.
EP has received consulting, speaker fees or grants from the fol-
lowing companies: Menarini, AstraZeneca, Savient, Procaps and
Novartis.
MA and JVM declare that they have no competing interest.
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