Vol.:(0123456789)1 3
Clinical Rheumatology
https://doi.org/10.1007/s10067-023-06578-9
REVIEW ARTICLE
The Hong Kong Society ofuni00A0Rheumatology consensus
recommendations foruni00A0theuni00A0management ofuni00A0gout
Ronalduni00A0MLuni00A0Yip
1
uni00A0· Tommyuni00A0Tuni00A0Cheung
2
uni00A0· Houni00A0So
3
uni00A0· Juliauni00A0PSuni00A0Chan
2
uni00A0· Carmenuni00A0TKuni00A0Ho
4
uni00A0· Helenuni00A0HLuni00A0Tsang
4
uni00A0·
Carreluni00A0KLuni00A0Yu
5
uni00A0· Priscillauni00A0CHuni00A0Wong
3
uni00A0· for the Hong Kong Society of Rheumatology
Received: 2 December 2022 / Revised: 9 February 2023 / Accepted: 12 March 2023
? The Author(s) 2023
Abstract
Gout is one of the most common noncommunicable diseases in Hong Kong. Although effective treatment options are read-
ily available, the management of gout in Hong Kong remains suboptimal. Like other countries, the treatment goal in Hong
Kong usually focuses on relieving symptoms of gout but not treating the serum urate level to target. As a result, patients
with gout continue to suffer from the debilitating arthritis, as well as the renal, metabolic, and cardiovascular complications
associated with gout. The Hong Kong Society of Rheumatology spearheaded the development of these consensus recom-
mendations through a Delphi exercise that involved rheumatologists, primary care physicians, and other specialists in Hong
Kong. Recommendations on acute gout management, gout prophylaxis, treatment of hyperuricemia and its precautions,
co-administration of non-gout medications with urate-lowering therapy, and lifestyle advice have been included. This paper
serves as a reference guide to all healthcare providers who see patients who are at risk and are known to have this chronic
but treatable condition.
Keywords Consensusuni00A0· Goutuni00A0· Hong Kong Society of Rheumatologyuni00A0· Hyperuricemiauni00A0· Recommendations
Introduction
The global incidence and prevalence of gout has substan-
tially increased over the past decade [1], and this is no
exception in Hong Kong. A local population-based study
reported an increase in the crude incidence rate of gout from
113.05/100,000uni00A0person-years in 2006 to 211.62/100,000
person-years in 2016 [2]. Similarly, the crude prevalence
of gout has risen from 1.56% in 2006 to 2.92% in 2016
[2]. Population aging has contributed significantly to the
increased incidence and prevalence of gout in Hong Kong.
Over the past 20uni00A0years, the number of Hong Kong people
aged 65uni00A0years or above increased from 12.5% to 16.1%. In
addition, modifiable risk factors for gout and hyperuricemia,
such as regular alcohol consumption, greater meat intake,
and obesity, have been increasing. As a result, the Hong
Kong government has included gout, alcohol drinking, and
obesity among the target non-communicable diseases in its
campaign programs for primary prevention [3]. However,
the management of gout in Hong Kong is yet to be improved.
The treatment goal usually focuses on relieving symp-
toms of arthritis but not treating the underlying hyperurice-
mia. Despite the availability and demonstrated efficacy of
urate-lowering therapy (ULT) in reducing serum uric acid
(SUA) levels, only 25.55% of all gout patients received
ULT and only 35.8% of these patients achieved the target
SUA level of < 0.36uni00A0mmol/L (6uni00A0mg/dL). Almost all gout
patients received allopurinol because it is subsidized by the
government. Other unsubsidized ULT options, including
febuxostat, were prescribed to < 1% of all gout patients [2].
Resolving the unmet need for the management of hyper-
uricemia and gout is challenging, because this includes
Ronald ML Yip
ronald.yip@tungwah.org.hk
1
Tung Wah Group ofuni00A0Hospitals Integrated Diagnostic
anduni00A0Medical Centre, Kwong Wah Hospital, 25, Waterloo
Road, Kowloon, Honguni00A0Kong
2
Rheumatology Centre, Department ofuni00A0Medicine, Hong Kong
Sanatorium & Hospital, Happyuni00A0Valley, Honguni00A0Kong
3
Department ofuni00A0Medicine anduni00A0Therapeutics, The Chinese
University ofuni00A0Hong Kong, Mauni00A0Liuuni00A0Shui, Honguni00A0Kong
4
Division ofuni00A0Rheumatology anduni00A0Clinical Immunology, Queen
Mary Hospital, Pokuni00A0Fuuni00A0Lam, Honguni00A0Kong
5
Hong Kong Autoimmune anduni00A0Rheumatic Diseases Centre,
Central, Honguni00A0Kong
Clinical Rheumatology
1 3
certain patient factors, such as pharmacologic compliance,
adverse reactions, and lack of health literacy, and healthcare
provider factors, such as under-recognition of over-produc-
ers and/or under-excretors, as well as knowledge gaps in
gout management [4, 5].
Although several international guidelines for the man-
agement of gout are available, there are certain differences
according to their ethnic, genetic, social, and cultural back-
ground, clinical practice, and the availability of medicine
[6–10]. The Hong Kong Society of Rheumatology (HKSR),
a professional organization that has been at the helm of train-
ing and improving the care of patients with rheumatic dis-
eases in Hong Kong, spearheaded the development of these
consensus recommendations aiming at improving the acute
and long-term management of gout, particularly focusing
on aspects related to the clinical practice in Hong Kong.
It is hoped that these recommendations can offer guidance
to not only primary care practitioners, but also specialists
who regularly see patients who are at risk for gout and its
complications.
Method
Steering committee
Eight core members of the Gout Special Interest Group
(Gout SIG) from the HKSR met through several rounds of
teleconferences from July 2020 onwards to discuss proposed
consensus recommendations relevant to the management of
gout in Hong Kong. Priority areas covered during the meet-
ings included: (1) acute gout management, (2) gout prophy-
laxis, (3) treatment of hyperuricemia, (4) co-administration
of non-gout medications with ULT, and (5) lifestyle modifi-
cations aimed at reducing SUA. A total of four overarching
principles anduni00A024 major recommendations were reviewed
and tweaked. A systematic literature search was concurrently
performed to identify and grade the relevant level of evi-
dence for each recommendation.
Literature search anduni00A0grading ofuni00A0evidence
Evidence for the consensus statements was identified
through an online search of the Medline database with the
search terms “acute gout therapy,” “clinical practice guide-
lines,” “gout,” “gout prophylaxis,” “hyperuricemia,” “life-
style modification,” “precaution,” “urate lowering therapy,”
and “non-pharmacological management” and other relevant
key words in the statements. Studies included were pub-
lished in the past 10uni00A0years including systematic reviews,
meta-analyses, clinical trials, cohort studies, and clinical
practice guidelines published in English. The level of evi-
dence of each statement was evaluated based on the Oxford
Centre for Evidence-Based Medicine system (Tableuni00A01) [11].
Consensus formation
Practicing rheumatologists registered as full members of
the HKSR and a selected group of family physicians, renal
physicians, and internists with special interest and exten-
sive clinical experience in gout management were invited to
participate in a modified Delphi exercise. Each overarching
statement and all major statements were sent to the partici-
pants for voting through anonymized online surveys. The
eight core members of the steering committee were excluded
from the voting sessions to avoid bias and skewing of the
results. The participants were provided with the results of
the literature search, explanatory notes, and the level of evi-
dence grading. For each statement, the members were asked
to share their level of agreement (strongly agree, agree, neu-
tral, disagree, and strongly disagree) using an online plat-
form hosted by MIMS, an independent medical communi-
cations company. They were also invited to give feedback
on the statements, indicate reasons for disagreement, and
Table 1 The Oxford Centre
for Evidence-Based Medicine
system for grading level of
evidence [11]
RCT Randomized controlled trial
Level Type of evidence
1A Systematic review (with homogeneity) of RCTs
1B Individual RCT (with narrow confidence intervals)
1C All or none study
2A Systematic review (with homogeneity) of cohort studies
2B Individual cohort study (including low-quality RCT, e.g., < 80% follow-up)
2C “Outcomes” research; ecological studies
3A Systematic review (with homogeneity) of case–control studies
3B Individual case–control study
4 Case series (and poor-quality cohort and case–control study)
5 Expert opinion without explicit critical appraisal or based on physiology
bench research or “first principles”
Clinical Rheumatology
1 3
suggest edits or improvements. Consensus was defined as an
agreement (strongly agree or agree) of uni2265 80% by the Delphi
participants. The anonymized voting results and feedback
were then communicated to the core members. Statements
that did not meet consensus were then either removed or
modified and redeployed to the Delphi participants along
with brief elucidatory notes for the subsequent rounds of
voting until consensus was reached.
Results
A total of 84 full HKSR members and 11 practitioners from
various specialties were invited. Overall, 60 participated in
the Delphi process. The group consisted of 83% rheuma-
tologists, 9% renal medicine specialists, 5% general practi-
tioners, and 3% internists. Among the HKSR members, the
response rate was 60% (50 of 84 eligible practicing rheu-
matologists). After two rounds of voting, consensus was
reached for all overarching statements and for 20 of the 24
major statements. The results of the voting for rounds 1 and
2 are summarized in Tablesuni00A02 and 3, respectively.
Overarching principles
These unifying themes include general recommendations
on lifestyle and educational interventions, and the adequate
management of comorbidities. These endeavors are typically
included in health literacy campaigns to prevent and control
the symptoms and complications of gout [3].
A. “Where possible, every patient with gout should be edu-
cated about the pathophysiology of the disease, treat-
ment options for gouty arthritis, its associated comor-
bidities, and indications of urate-lowering agents.”
Most studies cite suboptimal understanding of gout and
its treatment as a common barrier to gout care. Physicians
should effectively communicate to their patients the direct
causal role of hyperuricemia to gout and gouty arthritis and
its comorbidities, as well as the treatable nature of the dis-
ease [12].
B. “Every patient with gout should receive advice from
their healthcare professionals regarding lifestyle modi-
fication and its role in the management of gout.”
Although gout is considered as a chronic and potentially
progressive condition requiring long-term management,
many people with gout falsely regard gout as an episodic
illness and are thus prone to poor medication compliance
and lack of treatment response or paradoxical attacks [12]. It
is thus crucial to discuss the treatment plan with patients to
lessen the risk of gout attacks and the metabolic complica-
tions associated with hyperuricemia [3].
III. “Apart from rheumatologists, non-rheumatologist
physicians and/or general practitioners should be
responsible for managing patients with gout. How-
ever, rheumatologists should provide specialist care
for patients with gouty arthritis refractory to treat-
ment with first-line therapies or those who fail to
achieve the treatment target despite appropriate use
of ULT.”
The continued partnership between patients and primary
care and other health professionals plays an important role in
monitoring and improving the management of gout in Hong
Kong [3]. Rheumatologists are often called in to reinforce
the management of gout patients; they determine whether
gout is the cause of arthritis and provide specialist advice
to further enhance education on adherence and continued
monitoring of the signs and symptoms of gout.
IV. “Every patient with gout should be systematically
screened for associated comorbidities and cardio-
vascular risk factors.”
A systematic review by van Durme etuni00A0al. revealed that
hyperuricemia appears to be a risk indicator and is a compo-
nent of the metabolic syndrome, rather than an independent
risk factor for cardiovascular disease, but may nonetheless
contribute to a slight increase in cardiovascular risk. Renal
disease, on the other hand, appears to be markedly prevalent
among hyperuricemic patients and may therefore need to be
considered when administering ULT to at-risk patients [13].
Acute gout management
First-line options include colchicine, non-steroidal anti-
inflammatory drugs (NSAIDs), or glucocorticoids (e.g.,
oral, intra-articular, or intramuscular). The choice of treat-
ment is often dependent on the patient’s comorbidities and
overall disease severity [8, 10, 13–20]. Initial combination
therapy may be needed for patients experiencing severe pain
or attacks affecting multiple joints (Fig.uni00A01) [21], although the
combination of an NSAID with systemic glucocorticoid is
not recommended because of their additive toxicity.
Statement 1
“Acute flares of gout should be treated as early as pos-
sible, preferably within 12uni00A0h. Patients should be edu-
cated to self-medicate at the first warning symptoms.”
Level of evidence: 1B
Early management of flares (i.e., by self-initiated medica-
tion) is widely recommended by treatment guidelines based
Clinical Rheumatology
1 3
Table 2 First round voting results of the major consensus statements on gout management
Statements Level of
evidence
Agreement (%)
Overarching principles
uni00A0uni00A0? “Where possible, every patient with gout should be educated about the pathophysiology of the disease, treat-
ment options for gouty arthritis, its associated comorbidities, and indications of urate-lowering agents.”
NA 97
uni00A0uni00A0? “Every patient with gout should receive advice from their healthcare professionals regarding lifestyle modifica-
tion and its role in the management of gout.”
NA 100
uni00A0uni00A0? “Apart from rheumatologists, non-rheumatologist physicians and/or general practitioners should be responsible
for managing patients with gout. However, rheumatologists should provide specialist care for patients with
gouty arthritis refractory to treatment with first-line therapies or those who fail to achieve the treatment target
despite appropriate use of ULT.”
NA 95
uni00A0uni00A0? “Every patient with gout should be systematically screened for associated comorbidities and cardiovascular risk
factors.”
NA 97
Acute gout management
uni00A0uni00A0? “Acute flares of gout should be treated as early as possible, preferably within 12uni00A0h. Patients should be educated
to self-medicate at the first warning symptoms.”
1B 95
uni00A0uni00A0? “Colchicine, NSAIDs, or glucocorticoids (oral, intra-articular, or intramuscular) are recommended as first-line
therapy for gout flares.”
1B 88
uni00A0uni00A0? “The choice of drug(s) should be based on the presence of comorbidities, patient''s previous response to treat-
ments, the severity of flares, and the number and type of joint(s) involved.”
1B 98
uni00A0uni00A0? “Use topical ice as an adjuvant therapy for pain relief.” 1B 80
uni00A0uni00A0? “IL-1 inhibitors can be considered for treatment of gout flare in patients who have inadequate response to or are
contraindicated for standard treatment (including colchicine, NSAIDs, and/or glucocorticoids). IL-1 inhibitors
are contraindicated in patients with active infection.”
1B 82
Gout prophylaxis
uni00A0uni00A0? “Prophylaxis with colchicine 0.5uni00A0mg once or twice daily for 3–6uni00A0months is recommended during initiation or
up-titration of ULT.”
2B 90
uni00A0uni00A0? “In patients who cannot tolerate colchicine, a low-dose NSAID can be used provided there are no contraindica-
tions.”
2B 75
uni00A0uni00A0? “IL-1 inhibitors may be considered as second-line treatment for gout prophylaxis in patients who are contrain-
dicated for colchicine or NSAIDs. However, their costs and putative infection risks may preclude their use as
first-line prophylactic agent.”
2B 68
Indications for ULT
uni00A0uni00A0? “ULT should be discussed with all patients diagnosed with gout.” 5 87
uni00A0uni00A0? “ULT should not be routinely recommended on the first attack of gout in patients without comorbidities.” 5 87
uni00A0uni00A0? “ULT should be recommended to all gout patients with tophi, radiographic damage related to gout, OR recur-
rent attacks (uni2265 2 times per year).”
1B 100
uni00A0uni00A0? “ULT can be considered in patients with gout after the first attack with urolithiasis, more than one flare but with
infrequent attacks per year, or in those with renal impairment.”
1B 97
uni00A0uni00A0? “ULT may be considered in patients with gout after the first attack with very high serum urate level
(> 0.54uni00A0mmol/L [9uni00A0mg/dL]) or young onset age (age < 40uni00A0years).”
1B 92
Treatment target of ULT
uni00A0uni00A0? “For patients on ULT, serum urate level should be monitored and maintained below 0.36uni00A0mmol/L (6uni00A0mg/dL). A
target SUA of < 0.30uni00A0mmol/L (5uni00A0mg/dL) is recommended for patients with tophaceous gout.”
3 95
uni00A0uni00A0? “When the clinical tophi have resolved, the serum urate level may be maintained between 0.30uni00A0mmol/L (5uni00A0mg/
dL) and 0.36uni00A0mmol/L (6uni00A0mg/dL).”
3 87
Precautions in prescribing allopurinol
uni00A0uni00A0? “Allopurinol should be avoided in patients who tested positive for HLA-B5801 allele.” 2B 97
uni00A0uni00A0? “Screening for the HLA-B5801 allele should be considered for some patients of Asian descent (e.g., Han
Chinese, Korean, Thai) and for African American patients, and patients with risk factors to develop allopurinol-
induced SCAR, before starting allopurinol. Risk factors included patients who are uni2265 60uni00A0years old or with renal
insufficiency (CKD stage uni2265 3).”
2B 92
uni00A0uni00A0? “Allopurinol desensitization may be considered for patients with a prior mild allergic response to allopurinol
who cannot be treated with other ULT and negative HLA-B5801 test.”
5 72
Use of ULT
uni00A0uni00A0? “A xanthine oxidase inhibitor (allopurinol or febuxostat) is the preferred agent for all patients with gout.” 1A 100
Clinical Rheumatology
1 3
on high-grade evidence [8, 10, 14–17]. Anti-inflammatory
therapy offers relief from pain and resolution of joint inflam-
mation when administered within 12uni00A0h of an attack. In par-
ticular, low-dose colchicine self-administered within 12uni00A0h
of flare onset has been shown to significantly reduce base-
line pain without the associated gastrointestinal side effects
associated with high-dose regimens [22]. Prompt treatment
might also ameliorate the risk for cardiovascular events
recently found to be associated with gout flares [23].
Statement 2
“Colchicine, NSAIDs, or glucocorticoids (oral, intra-
articular, or intramuscular) are recommended as first-
line therapy for gout flares.”
Level of evidence: 1B
Colchicine can be given at a loading dose of 1uni00A0mg, fol-
lowed by 0.5uni00A0mg 1uni00A0h later on day 1; subsequent doses can be
given at 0.5uni00A0mg twice or three-times daily until symptoms
subside, or intolerable side effects occur. A gout flare gen-
erally warrants a higher dose of NSAID. However, treat-
ment should be continued for the shortest possible duration
needed to fully control the attack (typically 3–5uni00A0days) and to
Table 2 (continued)
Statements Level of
evidence
Agreement (%)
uni00A0uni00A0? “If the targeted serum urate level cannot be achieved by allopurinol, febuxostat should be considered. Alterna-
tively, combination therapy with a uricosuric agent can be considered in patients without severe renal impair-
ment (GFR < 30uni00A0mL/min).”
1A 93
Co-administration of non-gout medications with ULT
uni00A0uni00A0? “Calcium channel blockers and losartan are preferred over other antihypertensive drugs e.g., loop or thiazide
diuretics, beta-blocker, angiotensin-converting enzyme inhibitors, and non-losartan angiotensin II receptor
blockers in patients with gout.”
3 77
uni00A0uni00A0? “For patients with gout who are receiving low-dose aspirin (< 300uni00A0mg daily) alone or in combination with
clopidogrel or ticagrelor for prevention or treatment of cardiovascular disease, serum uric acid levels should be
regularly monitored and appropriate ULT adjustment should be made accordingly.”
5 67
Lifestyle modification
uni00A0uni00A0? “Patients should be advised to avoid alcohol, fructose, or sugar-sweetened beverages, and decrease dietary
protein source from meat and seafood.”
2B 88
uni00A0uni00A0? “Weight reduction is recommended if BMI > 25uni00A0kg/m
2
.” 2B 97
BMI Body mass index; CKD Chronic kidney disease; GFR Glomerular filtration rate; HLA Human leukocyte antigen; IL-1 Interleukin-1; NSAID
Non-steroidal anti-inflammatory drug; SCAR Severe cutaneous adverse reaction; SUA Serum uric acid; ULT Urate-lowering therapy
Table 3 Second round voting
results of the major consensus
statements on gout management
NSAID Non-steroidal anti-inflammatory drug
Statements Level of evidence Agreement
Gout prophylaxis
uni00A0uni00A0? “In patients who cannot tolerate colchicine, a low-dose NSAID
can be considered as an alternative for prophylaxis after weighing
the risks and benefits.”
2B 84
Alternate
options
Re-assessment
and follow-up
Treatment
response
Choice of
monotherapy
Initial treatment
of acute gout
Initial
consultation
Assessment of
patient
comorbidities and
gout severity
Initial combination
therapy for severe
pain or attacks
affecting multiple joints
Monotherapy (with or
without topical
icetherapy)
NSAID or COX-2 inhibitors or
colchicine or glucocorticoids
(e.g., oral, intra-articular, or
intramuscular)
Inadequate
response
Switch to alternate
monotherapy OR
consider add-on
combination therapy
Consider IL-1
inhibitors, alternate
options, and further
investigation
Successful
treatment
Patient education and
lifestyle advice AND
consider ULT or adjustment
of current ULT regimen
Fig. 1 Consensus recommendations on the management of acute gout
attack [6]. COX, cyclooxygenase; IL,uni00A0interleukin; NSAID, non-steroi-
dal anti-inflammatory drug; ULT, urate-lowering therapy
Clinical Rheumatology
1 3
prevent recurrence. One potential advantage of NSAIDs is
their analgesic effect, which may reduce pain before inflam-
mation subsides. The typical glucocorticoid regimen is oral
prednisolone 30uni00A0mg/day or 0.5uni00A0mg/kg for 5uni00A0days or tapered
over 7–14uni00A0days. Joint aspiration and injection of intra-
articular glucocorticoids are particularly indicated in flares
affecting large joints or where there are other differential
diagnoses [8, 10, 14–20, 24, 25].
Statement 3
“The choice of drug(s) should be based on the pres-
ence of comorbidities, patient''s previous response to
treatments, the severity of flares, and the number and
type of joint(s) involved.”
Level of evidence: 1B
Colchicine dose should be reduced in patients with renal
impairment and avoided in patients with severe renal impair-
ment (glomerular filtration rate [GFR] < 30uni00A0mL/min) or in
those receiving strong P-glycoprotein and/or cytochrome
P450 (CYP) 3A4 inhibitors such as cyclosporin or clarithro-
mycin. The concomitant use of statins may also increase
the risk of myopathy and rhabdomyolysis. Evidence does
not support the preferred use of any one NSAID, includ-
ing cyclooxygenase-2 inhibitors, over another, so selection
should be based on the patient’s prior response and con-
cern over specific side effects. NSAIDs should be avoided
in patients with renal impairment. Finally, systemic gluco-
corticoids are useful in acute, severe, and/or polyarticular
attacks. A single dose of intramuscular glucocorticoids can
be given, especially when a more rapid effect is desired.
Intra-articular glucocorticoid injections are useful in patients
with severe attacks involving one or two joints, especially in
large weight-bearing joints [8, 10, 14–20, 24, 25].
Statement 4
“Use topical ice as an adjuvant therapy for pain relief.”
Level of evidence: 1B
In a small, randomized study of 19 patients with acute
gout, the group treated with ice reported greater reduction
in pain compared with patients in the control group. Both
groups were also given prednisolone and colchicine [26].
Statement 5
“Interleukin-1 (IL-1) inhibitors can be considered for
treatment of gout flare in patients who have inadequate
response to or are contraindicated for standard treat-
ment (including colchicine, NSAIDs, and/or glucocor-
ticoids). IL-1 inhibitors are contraindicated in patients
with active infection.”
Level of evidence: 1B
IL-1 inhibitors may be used in refractory polyarticular or
tophaceous gout or for patients who are unable to tolerate
conventional therapy for acute flares. These agents have been
evaluated in case series and small randomized controlled
trials/based on a low to moderate level of evidence. These
agents may be an option in patients with chronic kidney dis-
ease (CKD), but its associated potential infectious compli-
cations and cost/benefit ratio must be carefully considered.
Anakinra, an IL-1 receptor antagonist that inhibits the activ-
ity of both IL-1uni03B1 and IL-1uni03B2, is effective in reducing acute
gout pain and inflammation and may be a reasonable option
in patients with CKD [27–32]. Rilonacept, a soluble decoy
receptor that binds to IL-1uni03B2, may be used to reduce the risk
of recurrent attacks [33]. Canakinumab may be an effective
option in reducing both pain in acute attacks and the risk of
recurrent attacks [34–36].
Gout prophylaxis
Moderate quality evidence supports the administration of
agents for flare prophylaxis, mainly with colchicine, among
patients being treated with ULT during the first 6uni00A0months
[8, 37–41].
Statement 6
“Prophylaxis with colchicine 0.5uni00A0mg once or twice
daily for 3–6uni00A0months is recommended during initia-
tion or up-titration of ULT.”
Level of evidence: 2B
Colchicine should be used with caution in patients with
renal or hepatic impairment. In patients receiving medica-
tions that inhibit CYP3A4 and/or the P-glycoprotein e?ux
pump, dosage adjustment or avoidance of colchicine is war-
ranted [42].
Statement 7
“In patients who cannot tolerate colchicine, a low-dose
NSAID can be considered as an alternative for prophy-
laxis after weighing the risks and benefits.”
Level of evidence: 2B
Alternate regimens, such as low-dose NSAIDs, may be of
benefit in patients who may present with relative or absolute
contraindications to colchicine therapy. However, the routine
use of low-dose NSAIDs, glucocorticoids, as well as IL-1
inhibitors for gout prophylaxis is not currently supported by
strong evidence [8, 43–46]; therefore, careful consideration
of the risks and benefits (i.e., not only evaluation of contrain-
dications) may be clinically relevant in certain populations.
Clinical Rheumatology
1 3
Indications foruni00A0urate-lowering therapy
Clinical trials have demonstrated that ULT is effective in
treating patients with recurrent flares, tophi, urate arthropa-
thy, and/or renal stones [47–69].
Statement 8
“ULT should be discussed with all patients diagnosed
with gout.”
Level of evidence: 5
As suboptimal understanding of gout and its treatment
poses as a common barrier to gout care, the core group con-
sidered early introduction of ULT to patients would serve as
an important education strategy in the management of gout.
Statement 9
“ULT should not be routinely recommended on the
first attack of gout in patients without comorbidities.”
Level of evidence: 5
The usefulness of ULT in patients diagnosed with gout is
most apparent in patients with recurrent gouty arthritis and
with associated signs and symptoms of either tophaceous or
non-tophaceous arthropathy [69, 70]. It is not particularly
advised for patients who experience a single, isolated epi-
sode of pain or joint swelling to receive ULT. A study by Yu
and Gutman documented that only 62% of patients with gout
had a second attack within a year [71]. A Canadian study
showed that gout treatment only becomes cost-effective in
patients who experience at least three attacks per year [70].
Therefore, ULT should be reserved for patients who have
documented organ affectation or in those who experience
frequent flares. On the other hand, there is also fear of delay-
ing the initiation of ULT until the second or third attack,
exposing patients to a higher crystal load, which may be
deleterious for the cardiovascular system and kidneys [8,
10]. Therefore, the panel considers that in selected patients
who prefer to start treatment after thorough discussions on
the risks and benefits, ULT might remain an option.
Statement 10
“ULT should be recommended to all gout patients with
tophi, radiographic damage related to gout, OR recur-
rent attacks (uni2265 2 times per year).”
Level of evidence: 1B
High-quality evidence from a randomized controlled
trial and as confirmed by a meta-analysis demonstrated
that ULT can reduce tophi size and numbers [48, 54].
Various authorities set a range of 0–3 attacks a year, but
most guidelines have adopted a strategy of initiating ULT
after two attacks per year [8, 10, 14–17].
Statement 11
“ULT can be considered in patients with gout after
the first attack with urolithiasis, more than one flare
but with infrequent attacks per year, or in those with
renal impairment.”
Level of evidence: 1B
In patients with a history of urolithiasis or those experi-
encing calcium oxalate renal stones and/or hyperuricosuria,
ULT has been documented to provide benefit by lowering
24-h urinary uric acid excretion more significantly than pla-
cebo [55, 56]. The 3-year incidence of stone-related events
was shown to decrease in those treated with allopurinol
vs. those treated with placebo [57]. However, the benefit
of ULT appears to decrease in patients with less frequent
flares compared with when ULT is prescribed to patients
with more frequent flares. Dalbeth etuni00A0al. demonstrated that
patients with at the most two previous flares and nouni00A0more
than one attack in the preceding year were less likely to
experience a subsequent flare (30% with febuxostatuni00A0vs.
41%uni00A0with placebo; p < 0.05) [58]. Hence, the number of
gouty attacks should be carefully considered before the
decision to start ULT is reached. In addition, renal disease
should likewise influence the decision to start ULT. Both
allopurinol and febuxostat has been documented to lower
24-h urinary uric acid excretion [56]. Allopurinol is also
known to slow the progression of CKD in hyperuricemia
patients. Because there is a higher likelihood of gout pro-
gression and tophi development in patients with CKD com-
pared with those with no renal impairment, this population
may benefit from early initiation of ULT [59–64].
Statement 12
“ULT may be considered in patients with gout after
the first attack with very high serum urate level
(> 0.54uni00A0 mmol/L [9uni00A0 mg/dL]) or young onset age
(age < 40uni00A0years).”
Level of evidence: 1B
The risk of gout rises sharply when serum urate levels are
above 0.5uni00A0mmol/L (8.4uni00A0mg/dL). Patients with markedly ele-
vated serum urate levels > 0.54uni00A0mmol/L (9uni00A0mg/dL) are more
likely to experience gout progression than those with lower
levels [66, 67, 69, 72]. Young age is a marker of severity
and may be associated with an inborn error of metabolism
or dysfunctional variant in the urate transporter [73–76].
Clinical Rheumatology
1 3
Treatment target ofuni00A0urate-lowering therapy
There is sparse evidence from randomized trials that estab-
lishes the treat-to-target approach in gout. However, data
from observational studies, including longer extension
studies, appear to suggest that SUA < 0.36uni00A0mmol/L (6uni00A0mg/
dL) was associated with reduced gout flares [69, 77–81].
Statement 13
“For patients on ULT, serum urate level should be
monitored and maintained below 0.36 mmol/L (6
mg/dL). A target SUA of <0.30 mmol/L (5 mg/dL)
is recommended for patients with tophaceous gout.”
Level of evidence: 3
The aim of ULT is to reduce and maintain the serum
urate level to prevent further urate crystal formation, to
dissolve existing crystals, and to prevent recurrent flares.
The lower the serum urate level, the greater the velocity
of crystal elimination [69, 77–82].
Statement 14
“When the clinical tophi have resolved, the serum
urate level may be maintained between 0.30uni00A0mmol/L
(5uni00A0mg/dL) and 0.36uni00A0mmol/L (6uni00A0mg/dL).”
Level of evidence: 3
The recommendation of a less stringent targeted
serum urate level of between 0.30uni00A0mmol/L (5uni00A0mg/dL) and
0.36uni00A0mmol/L (6uni00A0mg/dL) after clinical tophi have resolved
is based on the possibility of adverse effects that may be
associated with a very low SUA level [69, 77–82]. Stud-
ies have shown that hyperuricemia might protect against
various neurodegenerative disorders such as Parkinson’s
disease and dementia, among others, and should therefore
be a strong consideration among elderly patients with gout
[83, 84].
Precautions inuni00A0prescribing allopurinol
The human leukocyte antigen (HLA)-B5801 haplotype
is the strongest risk factor for allopurinol-induced severe
cutaneous adverse reactions (SCARs). Allopurinol-induced
SCARs include drug hypersensitivity syndrome, Ste-
vens–Johnson syndrome (SJS), and toxic epidermal necroly-
sis. Patients who experience SCARs after ULT often have a
poor prognosis. However, there are insufficient data to estab-
lish firm recommendations for cost-effective screening in
populations with low allele frequency [17, 85–98].
Statement 15
“Allopurinol should be avoided in patients who have
tested positive for HLA-B5801 allele.”
Level of evidence: 2B
As mentioned, HLA-B5801 haplotype is the strongest risk
factor for allopurinol-induced SCARs.uni00A0Screening for HLA-
B5801 is beneficial in populations with high rates of allopu-
rinol-induced toxic epidermal necrolysis/SJS, especially in
populations with a higher frequency of the allele (uni2265 5%) [92].
Statement 16
“Screening for the HLA-B5801 allele should be
considered for some patients of Asian descent (e.g.,
Han Chinese, Korean, Thai) and for African Ameri-
can patients, and patients with risk factors to develop
allopurinol-induced SCAR, before starting of allopu-
rinol. Risk factors included patients who are uni226560 years
old or with renal insufficiency (CKD stage uni22653).”
Level of evidence: 2B
Certain populations particularly benefit from genetic
testing for HLA-B5801 before allopurinol administra-
tion because of the high potential cost-effectiveness of this
intervention. In a local study, Wong etuni00A0al. suggested that
pre- treatment HLA-B5801 screening is cost-effective in
Chinese patients with CKD to prevent allopurinol-induced
SCARs [99]. Apart from consideration of ethical, legal,
and social implications to land at informed policy decision-
making, awareness of risk factors, such as age or renal insuf-
ficiency, may be necessary to justify the appropriateness of
the utilization of this test [92–94, 96]. Stamp etuni00A0al. posit that
a starting dose of 1.5uni00A0mg per unit of estimated GFR may
reduce this risk [98]. The group suggests the use of alterna-
tive ULTs (e.g., febuxostat) in these patients.
Use ofuni00A0urate-lowering therapy
The use of ULT for the prevention of recurrent gout flares and
disease progression and the treatment of tophi is supported by
clinical trials/high level of evidence. The choice between xan-
thine oxidase inhibitors (XOIs) and/or uricosurics is depend-
ent on a patient’s clinical picture. These recommendations
are based on a moderate to high level of evidence [100–115].
Statement 17
“A xanthine oxidase inhibitor (allopurinol or febux-
ostat) is the preferred agent for all patients with gout.”
Clinical Rheumatology
1 3
Level of evidence: 1A
Allopurinol should be considered as the first-line agent
especially in patients with pre-existing major cardiovascu-
lar diseases. The starting and maximum dosage of allopu-
rinol should be adjusted according to creatinine clearance
in patients with renal impairment [100–115]. However, in
individuals who are observed to tolerate allopurinol, there
is evidence that gradually increasing the dose above doses
based on kidney function is safe and effective in those with
chronic kidney disease [116, 117]. There is no evidence that
limiting the maintenance dose reduces the risk of allopurinol
hypersensitivity syndrome [118].
Statement 18
“If the targeted serum urate level cannot be achieved
by allopurinol, febuxostat should be considered. Alter-
natively, combination therapy with a uricosuric agent
can be considered in patients without severe renal
impairment (GFR <30 mL/min).”
Level of evidence: 1A
Observational and cohort studies have shown that the use
of febuxostat in patients with CKD stages 3–5 was not asso-
ciated with increased adverse events but conferred more sig-
nificant reduction in serum urate levels vs. allopurinol [100,
103]. Results of the Cardiovascular Safety of Febuxostat and
Allopurinol in Participants With Gout and Cardiovascular
Comorbidities (CARES) trial, highlight the noninferior-
ity of febuxostat vs. allopurinol as regards rates of adverse
cardiovascular events [119]. Although this study posits that
all-cause mortality and cardiovascular mortality were higher
with febuxostat than with allopurinol, the long-term Febux-
ostat versus Allopurinol Streamlined Trial (FAST) study
established that after a median follow-up of about 4uni00A0years,
febuxostat was not associated with a higher risk of death
or serious adverse events compared with allopurinol [120].
Hence, the presence of pre-existing major cardiovascular
diseases should not preclude the use of febuxostat in patients
who fail to achieve the treatment target with allopurinol
[101–103, 121].
The use of uricosuric monotherapy is not preferred unless
patients present with a contraindication or intolerance to
both XOIs. The use of allopurinol or febuxostat with a uri-
cosuric agent decreases the urate concentration in urine and
thus the risk of urolithiasis [109–115].
Lifestyle modification
Dietary interventions limiting red meat, seafood, sugary bev-
erages, and alcohol have been the cornerstone of lifestyle
management among patients who have gout. Also, moder-
ate to heavy physical activity and overall fitness have been
found to be associated with a lower incidence of gout and
hyperuricemia [122–125].
Statement 19
“Patients should be advised to avoid alcohol, fructose,
or sugar-sweetened beverages, and decrease dietary
protein source from meat and seafood.”
Level of evidence: 2B
A diet that restricts alcohol and purine-rich and fruc-
tose-rich foods, while maintaining the intake of low-fat
dairy products, healthy protein sources, and vegetables,
has been observed to lower the risk of incident gout [122].
Ethanol has been found to facilitate increased urate produc-
tion through acetate metabolism and enhanced adenosine
triphosphate turnover [126–128]. Moreover, beer contains
purines that have been found to intensify the plasma con-
centration of uric acid [129, 130]. Substantial intake of red
meat and seafood, or food stuffs with high purine content,
has been likewise positively correlated with the develop-
ment of hyperuricemia and gout flares [131]. In a study of
vigorously active men, those with higher alcohol intake (per
10uni00A0g/day) had a higher relative risk (RR) of 1.19 (95% confi-
dence interval [CI]: 1.12–1.26; p < 0.0001) and those with a
higher meat consumption (per servings/day) had a higher RR
(1.45; 95% CI: 1.06–1.92; p = 0.002), whereas those with
greater fruit intake (per piece/day) had a lower RR (0.73;
95% CI: 0.62–0.84; p < 0.0001). Men who consumed more
than 15uni00A0g of alcohol (in particular beer) per day had a 93%
higher risk and higher rates of SUA levels than those who
had abstained, and men who averaged more than two pieces
of fruit/day had cut their risk in half compared with those
who ate < 0.5uni00A0pieces of fruit/day and had comparative body
mass index (BMI) levels (RR: 1.19; 95% CI: 1.15–1.23;
p < 0.0001) [123, 132, 133]. Fructose metabolism leads to
an increase in purines, which are converted into uric acid.
Also, long-term fructose administration suppresses urinary
excretion of uric acid leading to hyperuricemia [134]. The
consumption of five to six servings of sugar-sweetened soft
drinks was associated with an increased multivariate RR
of 1.29 (95% CI: 1.00–1.68) compared with one serving a
month [135].
Statement 20
“Weight reduction is recommended if BMI > 25uni00A0kg/
m
2
.”
Level of evidence: 2B
A prospective cohort study of over 40,000 men with
excess adiposity and other key modifiable factors suggests
that weight control has the potential to prevent most inci-
dent gout cases among men. The authors of the study state
Clinical Rheumatology
1 3
that men with obesity may not respond to gout therapy
unless weight loss is achieved [122]. In a separate study, the
risk of gout was noted to be 16-fold greater for men with
BMI > 27.5uni00A0kg/m
2
than in those who had a BMI < 20uni00A0kg/
m
2
. In addition, compared with those who were least active
or fit, men who ran uni2265 8uni00A0km/day or > 4.0uni00A0m/s had 50% and
65% lower risk of gout, respectively [136]. A systematic
review by Nielsen etuni00A0al. showed that low to moderate grade
evidence supports weight loss in overweight gout patients
achieve SUA targets and have fewer gout attacks at medium-
term or long-term follow-up on SUA [137]. Overall, obesity
has an impact on both incidence and control of gout.
Discussion
This set of HKSR consensus recommendations for gout
management encompasses lifestyle and medical interven-
tions that offer guiding provisions for primary care and
specialist clinicians to aid in lowering the risk of gout and
hyperuricemia in their patients. The 60 members of the vot-
ing faculty represented practicing rheumatologists, renal
medicine specialists, general practitioners, and internists in
the locality. To date, this paper is the first consensus docu-
ment on gout management involving most practicing rheu-
matologists in Hong Kong. The voting panel included over
80% of local practicing rheumatologists. The final recom-
mendation statements consider existing evidence and local
viewpoints to aid in the optimization of gout and hyperurice-
mia control in Hong Kong. The individual recommendations
have been enumerated in logical sequence and are intended
to guide practitioners in administering appropriate medical
treatment coupled with non-pharmacologic interventions,
involving several aspects of care that are of particular con-
cern in the locality. For instance, screening for HLAB-5801
was emphasized and may be justified as standard practice in
our clinical setting. In addition, the introduction of newer
agents in our locality, such as IL-1 inhibitors for acute gouty
attacks in complicated cases and the use of ULT for chronic
cases, was included. In most cases, gout and hyperuricemia
can be managed in the primary care setting. Patients who are
refractory to standard care may require specialist manage-
ment and should be referred as and when necessary.
Treatment of acute gout remains largely dependent on
the severity and the clinical profile of patients. Prompt
therapy of acute attacks with colchicine, NSAIDs, or glu-
cocorticoids is considered, but with careful watch over
comorbidities, especially renal disease. Although evidence
supports the use of IL-1 inhibitors for gout prophylaxis
[43–46], the use of canakinumab and rilonacept may
be precluded by their costs and putative infection risks.
The group has considered these factors and emphasizes
that the availability of these agents should be taken into
consideration when administered as first-line prophylaxis
for gout. Prophylaxis is currently limited to colchicine and
low-dose NSAIDs given to patients during initiation or
up-titration of ULT. ULT is effective in treating patients
with recurrent flares, tophi, urate arthropathy, and/or renal
stones, but not in all instances. A review of the patient’s
age, risk factors, current treatments, organ affectations,
signs and symptoms, and required treatment targets should
be conducted at the onset. Allopurinol remains a popular
choice for ULT across various populations. HLA-B5801
screening should be considered in high-risk patients
before initiation of allopurinol. The cost-effectiveness
of HLA-B5801 screening for preventive management
of SCARs should be evaluated before the determination
of the necessity for this intervention in low-risk patients
across the different centers and hospitals in Hong Kong.
Febuxostat may be considered as second-choice therapy in
those with known allopurinol-induced hypersensitivity or
adverse reactions. Recent guidelines recommend switch-
ing from febuxostat to other ULT options in patients with
a history of cardiovascular disease or new cardiovascular
events based on the results of the CARES trial [10, 119].
However, the results of this study pose uncertainties, and
data from subsequent exploratory analyses of the CARES
trial countered the contended association between febux-
ostat use and an increased mortality risk [138, 139]. More
recent studies have also established the safety of febux-
ostat after 4uni00A0years of use [120, 121]. Hence, the core mem-
bers of the steering committee suggest that the presence
of pre-existing major cardiovascular diseases should not
preclude the use of febuxostat in indicated patients.
The panel did not achieve consensus on recommendations
pertaining to co-administration of non-gout medications
with ULT after two rounds of voting. This may be related to
the relative lack of strong evidence [140–147]. However, as
reported by an epidemiologic study, the RRs of associated
incident gout were lower with current use of calcium channel
blockers and losartan. Hence, in gout patients, calcium chan-
nel blockers and losartan are preferred over other antihyper-
tensive drugs, e.g., loop or thiazide diuretics, beta-blockers,
angiotensin-converting enzyme inhibitors, and non-losartan
angiotensin II receptor blockers [140]. For patients with gout
who are receiving low-dose aspirin (< 300uni00A0mg daily) alone
or in combination with clopidogrel or ticagrelor for preven-
tion or treatment of cardiovascular disease, it is advisable to
monitor serum uric acid levels regularly, and make appropri-
ate ULT adjustment accordingly [141, 142]. The long-term
efficacy and safety of slow oral desensitization to allopu-
rinol are established for gout patients with maculopapular
eruptions who cannot be treated with uricosurics or another
ULT; however, it is not recommended in patients with severe
hypersensitivity to allopurinol. The panel recognizes that
desensitization protocols are not commonly used, with most
Clinical Rheumatology
1 3
currently practicing rheumatologists having limited experi-
ence in these protocols [97].
Finally, lifestyle modification is a cornerstone in the man-
agement of hyperuricemia and gout, and relevant patient
education regarding diet and exercise should be espoused
when treating these patients.
Local registry studies and trials looking at various aspects
of gout therapy may be worthwhile to consider. Other areas
of gout treatment, such as the usefulness of surgery and
other clinical aspects of care, should be investigated in future
studies. These new data may be useful in reshaping upcom-
ing recommendations to support the improvement of gout
care in Hong Kong. Likewise, optimization of treatment
approaches and holistic management of other metabolic
conditions may help in the overall improvement of patients
and should become the focus of future guidelines.
Acknowledgements We would like to thank all the HKSR full mem-
bers and those who participated in the Delphi exercise. We also would
like to thank MIMS for their editorial support in the preparation of
this manuscript.
Data Availability The data that support the findings of this study are
available with from the corresponding author with permission ofuni00A0the
Hong Kong Society of Rheumatology.
Declarations
Ethical standards The manuscript does not contain clinical studies or
patient data.
Disclosures None.
Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
included in the article''s Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in
the article''s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.
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