Annals of Internal Medicine
Management of Gout: A Systematic Review in Support of an American
College of Physicians Clinical Practice Guideline
Paul G. Shekelle, MD, PhD; Sydne J. Newberry, PhD; John D. FitzGerald, MD, PhD; Aneesa Motala, BA; Claire E. O’Hanlon, MPP;
Abdul Tariq, BS; Adeyemi Okunogbe, MD; Dan Han, MPA; and Roberta Shanman, MLS
Background: Gout is a common type of inflammatory arthritis in
patients seen by primary care physicians.
Purpose: To review evidence about treatment of acute gout at-
tacks, management of hyperuricemia to prevent attacks, and dis-
continuation of medications for chronic gout in adults.
Data Sources: Multiple electronic databases from January
2010 to March 2016, reference mining, and pharmaceutical
manufacturers.
Study Selection: Studies of drugs approved by the U.S. Food
and Drug Administration and commonly prescribed by primary
care physicians, randomized trials for effectiveness, and trials
and observational studies for adverse events.
Data Extraction: Data extraction was performed by one re-
viewer and checked by a second reviewer. Study quality was
assessed by 2 independent reviewers. Strength-of-evidence as-
sessment was done by group discussion.
Data Synthesis: High-strength evidence from 28 trials (only 3 of
which were placebo-controlled) shows that colchicine, non-
steroidal anti-inflammatory drugs (NSAIDs), and corticosteroids
reduce pain in patients with acute gout. Moderate-strength evi-
dence suggests that low-dose colchicine is as effective as high-
dose colchicine and causes fewer gastrointestinal adverse
G out, a common form of inflammatory arthritis, is
characterized by acute intermittent episodes of sy-
novitis that cause joint swelling and pain. Approxi-
mately 8 million persons in the United States have gout
(1). It occurs when excess urate in the body crystalizes
(as monosodium urate) in joint fluid, cartilage, bones,
tendons, bursas, or other sites. The crystals can directly
initiate an acute inflammatory attack. In some patients,
acute gout attacks become progressively more fre-
quent, protracted, and severe and may progress to a
chronic inflammatory condition. In addition, some pa-
tients develop tophi, which are deposits of urate crys-
tals at the surface of joints or in skin or cartilage.
This systematic review was proposed by the Amer-
ican College of Physicians (ACP) to support the devel-
opment of a clinical practice guideline that would aid
primary care practitioners in the management of adult
patients with gout.
METHODS
We developed a protocol (http://effectivehealthcare.
ahrq.gov/ehc/products/564/1992/Gout-managment-pro-
tocol-141103.pdf); followed PRISMA (Preferred Report-
ing Items for Systematic reviews and Meta-Analyses)
guidelines for reporting systematic reviews (2); and de-
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REVIEW
events. Moderate-strength evidence suggests that urate-
lowering therapy (allopurinol or febuxostat) reduces long-term
risk for acute gout attacks after 1 year or more. High-strength
evidence shows that prophylaxis with daily colchicine or NSAIDs
reduces the risk for acute gout attacks by at least half in patients
starting urate-lowering therapy, and moderate-strength evi-
dence indicates that duration of prophylaxis should be longer
than 8 weeks. Although lower urate levels reduce risk for recur-
rent acute attacks, treatment to a specific target level has not
been tested.
Limitation: Few studies of acute gout treatments, no placebo-
controlled trials of management of hyperuricemia lasting longer
than 6 months, and few studies in primary care populations.
Conclusion: Colchicine, NSAIDs, and corticosteroids relieve
pain in adults with acute gout. Urate-lowering therapy decreases
serum urate levels and reduces risk for acute gout attacks.
Primary Funding Source: Agency for Healthcare Research and
Quality. (Protocol registration: http://effectivehealth-care.
ahrq.gov/ehc/products/564/1992/Gout-managment-protocol-
141103.pdf)
Ann Intern Med. 2017;166:37-51. doi:10.7326/M16-0461 www.annals.org
For author affiliations, see end of text.
This article was published at www.annals.org on 1 November 2016.
tailed search and selection processes, inclusion criteria,
and evidence tables in an evidence report (3).
Key Questions
Key questions proposed by ACP were revised on
the basis of input from a group of key informants, a
technical expert panel, and the public. Treatment ques-
tions addressed benefits and harms of pharmacologic
and dietary therapies for adults with acute gout attacks
and the intermediate and long-term benefits and harms
of therapies for adults with gout and hyperuricemia.
Additional management questions addressed monitor-
ing of serum urate levels and whether criteria exist
to identify patients who are candidates for discontinua-
tion of urate-lowering therapy or anti-inflammatory
prophylaxis.
Data Sources and Searches
We searched (without language restrictions) for
systematic reviews and original research studies in
PubMed, EMBASE, the Cochrane Collaboration, and
See also:
Related articles. . . . . . . . . . . . . . . . . . . . . . . 27, 52, 58
Editorial comments . . . . . . . . . . . . . . . . . . . . . . 71, 73
© 2017 American College of Physicians 37
 REVIEW
the Web of Science, using the terms “gout” and “gouty”
and terms for tophi. The start date of the searches was
1 January 2010, which was at least 1 year before the
search dates for the most recent systematic reviews,
and the end date was 1 March 2016. Relevant refer-
ences were obtained from 29 recent systematic re-
views. We searched ClinicalTrials.gov from inception to
1 March 2016 and the Web of Science from 1 January
2010 through 1 March 2016, and we contacted manu-
facturers of prescription medications used to treat gout
for recently completed studies and unpublished or
non–peer-reviewed study findings in July 2014. Appen-
dix Table 1 (available at www.annals.org) provides de-
tailed search methods.
Study Selection
Two reviewers independently screened records
(titles, abstracts, and articles) to identify reviews and
studies that reported on the benefits (randomized tri-
als) or harms (observational studies and trials) of treat-
ment and management strategies for gout. We exam-
ined only medications approved by the U.S. Food and
Drug Administration (FDA), except for nonsteroidal
anti-inflammatory drugs (NSAIDs), which are commonly
used to treat gout. As suggested by the ACP Clinical
Guidelines Committee, we excluded pegloticase and
lesinurad, which primary care physicians are unlikely to
prescribe. Studies that enrolled participants with no for-
mal gout diagnosis (based on either synovial fluid anal-
ysis or a clinical diagnosis) were excluded.
Data Extraction and Quality Assessment
Study-level details were abstracted by one re-
viewer and checked by a second reviewer, with recon-
ciliation of disagreements by group discussion. Risk of
bias of individual studies was assessed independently
by 2 reviewers using an adapted Cochrane risk-of-bias
tool (4), with reconciliation of disagreements by the
project lead. A modified AMSTAR (A Measurement
Tool to Assess Systematic Reviews) tool was used to
assess the quality of systematic reviews (5).
Data Synthesis and Grading
We deemed studies to be too few in number and
too heterogeneous to support new meta-analysis. We
assessed the overall strength of evidence as high, mod-
erate, low, or insufficient for each conclusion by using
guidance suggested by the Effective Health Care Pro-
gram (6). We also applied criteria proposed by Brad-
ford Hill for causality when judging strength of evi-
dence (7), including the strength, consistency, and
specificity of the association; the temporal relationship;
the “biologic gradient” or dose–response curve; the bi-
ologic plausibility; and coherence.
Role of the Funding Source
This topic was proposed by the ACP to the Agency
for Healthcare Research and Quality (AHRQ) and
funded by AHRQ. Staff at AHRQ and ACP helped to
develop and refine the scope of the study and re-
viewed the draft report.
38 Annals of Internal Medicine • Vol. 166 No. 1 • 3 January 2017
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Systematic Review in Support of ACP Guideline on Management of Gout
RESULTS
The Figure shows the search and selection process
that identified 155 articles meeting the inclusion crite-
ria. Of these, 22 evaluated dietary therapy or traditional
Chinese medicine; details about the inconclusive evi-
dence from those studies are in the evidence report (3).
Pharmacologic Treatment for Acute Gout
We identified evidence for several pharmacologic
treatments for acute gout: colchicine, NSAIDs, cortico-
steroids, and animal-derived corticotropin formulation
(8 –35). None of the studies assessed differences
in effectiveness by patient characteristics, such as
age, sex, duration of the episode, history, genetic
profile, baseline serum urate level, or presence of
comorbidities.
Colchicine
Although colchicine was used to treat gout in the
ninth century or earlier (36), its use has been evaluated
in only 2 randomized, placebo-controlled trials (12, 14).
These trials enrolled 184 and 43 patients, respectively,
who had crystal-proven gout or met the American Col-
lege of Rheumatology criteria and had mean duration
of symptoms of 38 hours or less. Both studies found
that patients treated with colchicine had better pain re-
lief than placebo recipients (38% vs. 16% achieved a
50% decrease in target joint pain at 24 hours, and 41%
vs. 9% achieved a 50% decrease in baseline pain score
at 24 hours). The earlier trial, published in 1987, used
an initial colchicine dose of 1 mg followed by 0.5 mg
every 2 hours until symptom relief or adverse effects
occurred (14). All of the colchicine-treated patients had
gastrointestinal adverse effects by 24 hours, and 91%
reported adverse effects before achieving a 50% re-
duction in pain intensity. The later trial compared “low-
dose” (an initial dose of 1.2 mg followed by 0.6 mg 1
hour later) versus “high-dose” (an initial dose of 1.2 mg
followed by 0.6 mg per hour for 6 hours) colchicine
(12). Low-dose colchicine was as effective as high-dose
colchicine compared with placebo and was much bet-
ter tolerated; for example, 23% versus 77% of patients
receiving low- and high-dose therapy reported diar-
rhea, and 0% versus 19% of these patients reported
severe diarrhea (Table 1).
NSAIDs
One low-quality, placebo-controlled trial assessed
NSAIDs in patients with acute gout (30). This small
study assessed the effect of tenoxicam (40 mg once
daily) in 30 patients and found that a greater propor-
tion of those receiving tenoxicam than those receiving
placebo reported at least 50% improvement at 24
hours.
Sixteen randomized trials compared one NSAID
with another (8, 9, 11, 15–19, 21–23, 27–29, 31, 32).
Most studies found no statistically significant differ-
ences in outcomes between treatments, although only
3 studies enrolled more than 100 patients (9, 22, 23),
meaning that most studies were small and had limited
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 Systematic Review in Support of ACP Guideline on Management of Gout REVIEW

Figure. Literature flow diagram.

Abstracts identified for dual review (n = 7928)

References identified from previous systematic reviews
or guidelines: 233
Titles identified from RAND library searches: 7403
Gray literature: 0
ClinicalTrials.gov: 292

Abstracts excluded (n = 7226)

Not human subjects: 295
Not about gout or hyperuricemia associated with
gout: 1630
Not about gout diagnosis or management or did
not address key question: 3855
Study of risk factors for gout did not test possible
treatment: 89
No original data or non–systematic review
background: 508
Case reports: 287
Population not of interest: 75
No abstract: 199
Gout diagnosis only: 104
Biologics outside scope of review: 133
Duplicate data: 51

Total articles identified for full-text review

(n = 702)

Full-text articles excluded (n = 547)

Not human subjects: 2
Not about gout or hyperuricemia associated with
gout: 26
Not about gout diagnosis or management or did
not address key question: 156
Study of risk factors for gout that did not test
possible treatment: 18
No original data or non–systematic review
background: 97
Study design: 66
Case reports: 51
Population not of interest: 8
Gout diagnosis only: 6
Biologics outside scope of review: 64
No outcomes of interest: 11
No interventions of interest: 2
Duplicate data: 37
Article not found: 3

Articles included for data synthesis*

Acute gout (n = 49) Diet and lifestyle Treatment for Monitoring (n = 27) Criteria for
Included in this management† (n = 22) hyperuricemia (n = 62) Included in this discontinuation (n = 3)
analysis: 28 Included in this analysis: 9 Included in this
Included only in analysis: 27 Included only in analysis: 3
evidence report: 21 Included only in evidence report: 18
evidence report: 35

* The number of included studies for this article differs from the number of included studies in the evidence report (3) because this review did not
address all of the key questions addressed in the report.
† Results for this question are not included in this article. See the evidence report (3).

power to detect differences (Appendix Table 2, avail- als compared corticosteroids (3 oral, 2 intramuscular,
able at www.annals.org). and 1 intravenous) versus NSAIDs. These studies, which
enrolled 27 (20), 60 (13), 90 (24), 92 (33), 120 (10), and
Corticosteroids 416 (34) patients, found few differences in effectiveness
No published placebo-controlled trials assessed or adverse events between treatments. In one study of
oral corticosteroids for acute gout. Six randomized tri- oral corticosteroids, 90 patients presenting to the
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 REVIEW Systematic Review in Support of ACP Guideline on Management of Gout

Table 1. Key Trials of Treatments for Acute Gout

Study, Year Study Population Average Male, Symptom Participants, Comparison Duration Results
(Reference) Age, y % Duration n
Ahern et al, Patients with acute 59 93 Average: 38 h 43 1. Colchicine, 1 mg 48 h Proportion of patients
1987 (14) gout proven by followed by 0.5 with ≥50% pain
crystals in mg every 2 h relief:
synovial fluid until relief or At 24 h:
analysis intolerable Colchicine: 41%
adverse effects Placebo: 9%
2. Placebo At 48 h:
Colchicine: 73%
Placebo: 36%
Nausea and vomiting
at 24 h:
Colchicine: 100%
Placebo: 24%
(nausea only)
Terkeltaub et al, Patients with 52 95 Current 184 1. Colchicine, 1.2 24 h Proportion of patients
2010 (12) confirmed symptoms: mg followed by with ≥50% pain
previous <12 h 0.6 mg relief at 24 h:
diagnosis of 1 h later Low-dose
gout with ≥2 (“low-dose”) colchicine: 38%
gout attacks in 2. Colchicine, 1.2 High-dose
the prior 12 mo; mg followed by colchicine: 33%
9% had tophi 0.6 mg every Placebo: 16%
hour up to 6 h Gastrointestinal adverse
(“high-dose”) events:
3. Placebo Low-dose
colchicine: 26%
High-dose
colchicine: 77%
Placebo: 20%
Alloway et al, “All patients 62 100 Average: 3.2 d 27 1. Triamcinolone 30 d No significant difference
1993 (20) seen by the acetonide, in any outcome.
rheumatology 60 mg No adverse events in
section for acute intramuscularly either group.
gout during a 9 2. Indomethacin,
month period 50 mg 3 times
were asked to daily for ≥2 d
participate”
Zhang et al, Patients who met 53 97 <24 h 60 1. Betamethasone, 14 d Proportion of patients
2014 (13) ACR criteria for 7 mg reporting severe
acute gout intramuscularly or extreme pain
2. Diclofenac, at day 2:
75 mg twice Betamethasone: 10%
daily for 7 d Diclofenac: 30%
All time points
beyond 3 d had
no statistically
significant
differences
between groups.
Adverse events
related to the
study drug:
Betamethasone: 10%
Diclofenac: 20%
Man et al, Patients with acute 65 83 Average: 2.3 d 90 1. Diclofenac, 12 d Statistically significant
2007 (24) arthritis 75 mg difference of 1-mm
suggestive of intramuscularly; faster improvement
gout who indomethacin, on a 10-cm pain
presented to the 50 mg orally; scale, favoring
emergency acetaminophen, prednisolone, of
department 1 g orally; and a questionable
5-d prescription clinical
for an significance.
indomethacin Adverse effects:
taper Indomethacin: 63%
2. Prednisolone, Prednisolone: 27%
30 mg orally;
acetaminophen,
1 g; and
prednisolone,
30 mg/d for 5 d
Continued on following page

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 Systematic Review in Support of ACP Guideline on Management of Gout REVIEW

Table 1—Continued

Study, Year Study Population Average Male, Symptom Participants, Comparison Duration Results
(Reference) Age, y % Duration n
Janssens et al, Patients presenting 58 89 ≤1 d 120 1. Prednisolone, 35 5d No significant difference
2008 (10) to family mg/d for 5 d in outcomes
physicians with 2. Naproxen, 500 between groups.
acute mg twice daily No significant differences
monoarthritis for 5 d in reported adverse
who then had events between
crystal-proven groups.
gout
Siegel et al, “All patients 66 100 Average: 28 d 30 1. Corticotropin, 40 30 d More patients in the
1994 (26) presenting to the IU corticotropin group
rheumatology intramuscularly than the
service with 2. Triamcinolone triamcinolone
acute gout were acetonide, 60 acetonide group
asked to mg required reinjection
participate” intramuscularly due to inadequate
symptom relief (9 vs.
5; P = 0.11).
Equivalent duration to
100% resolution for
both groups (7.9 vs.
7.6 d).
Axelrod and Patients presenting 56 100 Duration of 76 1. Indomethacin, 1y Time to pain relief was
Preston, with acute onset pain: <24 h 50 mg 4 times faster in the
1988 (25) of pain and daily until pain corticotropin group
crystal-proven abated than in the
gout 2. Corticotropin, 40 indomethacin group
IU (3 vs. 24 h).
intramuscularly Adverse effects were
more common in
indomethacin-
treated patients.
Liu et al, Patients who met 44 97 1–3 d 92 1. Colchicine, 0.5 1 mo Proportion of patients
2015 (33) 1997 ACR mg twice daily, reporting treatment
criteria for acute and intravenous as markedly
gout dexamethasone, effective:
2.5 mg for 3 d At 6 h:
2. Colchicine, 1 mg Colchicine and
orally then 0.5 dexamethasone:
mg every 1–2 h 70%
for 24 h then 1 Colchicine: 28%
mg twice daily At 24 h:
for 3 d Colchicine and
dexamethasone:
85%
Colchicine: 70%
Adverse effects:
Colchicine and
dexamethasone: 0%
Colchicine: 76%
(nausea only)
Rainer et al, Patients presenting 65 74 Average: 2.8 d 416 1. Indomethacin, 14 d No statistically significant
2016 (34) to the 50 mg 3 times differences in pain
emergency daily for 2 d then scores at any time
departments of 4 25 mg 3 times point except in pain
Hong Kong daily for 3 d at rest on days 1–5.
hospitals who 2. Prednisolone, 30 No difference in overall
had symptoms mg/d for 5 d adverse effects.
lasting ≤3 d and 11.1% of
were considered indomethacin-
to have gout treated patients and
5.8% of
prednisolone-treated
patients had
abdominal pain.
ACR = American College of Rheumatology.

emergency department with acute arthritis suggestive
of gout were randomly assigned to receive either pred-
nisolone, 30 mg/d for 5 days, or indomethacin, 50 mg 3
times daily for 2 days and 25 mg/d for the next 3 days;
www.annals.org
all patients also received paracetamol. No statistically
or clinically significant between-group differences were
seen at any evaluation point (up to 14 days). More pa-
tients in the indomethacin group than the prednisolone
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 REVIEW
group reported adverse events (63% vs. 27%) (24). In
another study of oral corticosteroids, 120 patients who
presented to family physicians with acute monoarthritis
and had monosodium urate crystals on synovial fluid
examination were randomly assigned to prednisolone,
35 mg/d, or naproxen, 500 mg twice daily. Over the
subsequent 4 days, no statistically significant differ-
ences in effectiveness outcomes were observed be-
tween groups. Equal proportions of patients in both
groups reported an adverse event (66% vs. 63%) (10).
The third study of oral corticosteroids randomly as-
signed 416 patients with a clinical diagnosis of gout
with symptoms lasting less than 3 days to indomethacin
or prednisolone for 5 days. There were no important
statistically or clinically significant differences in pain
outcomes or overall adverse events. Gastrointestinal
adverse events were more common in the
indomethacin-treated patients, and skin rash was more
common in the prednisolone-treated patients (34)
(Table 1).
Corticotropin
No published placebo-controlled trials tested cor-
ticotropin for acute gout. Two randomized, controlled
trials compared intramuscular corticotropin versus
other active agents. One evaluated corticotropin, 40 IU,
versus triamcinolone, 60 mg, both given intramuscu-
larly only once (26); the other evaluated corticotropin,
40 IU once, versus indomethacin, 50 mg 4 times a day
until pain abated (25). In the former study, patients
treated with triamcinolone required fewer reinjections
for inadequate pain relief than those treated with corti-
cotropin at up to 30 days of follow-up (5 vs. 9 patients;
P = 0.11). In the latter study, pain relief was faster with
corticotropin than with oral indomethacin (3 vs. 24
hours to total pain relief), and at the dose of 50 mg 4
times a day, 55% of indomethacin-treated patients re-
ported gastrointestinal adverse events (no adverse
events were reported by patients receiving corticotro-
pin) (Table 1).
Summary
Despite the small number of placebo-controlled tri-
als, we judged the strength of evidence as high that
colchicine, NSAIDs, and corticosteroids relieve pain in
patients with acute gout, based on the known physiol-
ogy of gout, the known mechanism of action of these
drugs, the proven effectiveness of these medications in
other painful or inflammatory conditions, and evidence
of equivalence in head-to-head trials of patients with
acute gout. We judged the evidence for use of cortico-
tropin to be of moderate strength because of high risk
of bias in the only 2 head-to-head randomized trials.
Pharmacologic Management of Hyperuricemia
in Patients With Gout
We found 11 systematic reviews (37– 47), 1 meta-
analysis (48), 1 new abstract (49), 5 secondary analyses
(50 –54) of trials already included in the systematic re-
views, 9 new trials assessing effectiveness (55– 63), and
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Systematic Review in Support of ACP Guideline on Management of Gout
26 studies of adverse effects that addressed this ques-
tion (64 – 89). Four large randomized trials of febuxostat
provided most of the effectiveness evidence: APEX
(Allopurinol- and Placebo-Controlled Efficacy Study of
Febuxostat) (90), FACT (Febuxostat versus Allopurinol
Controlled Trial) (91), the CONFIRMS (Confirmation of
Febuxostat in Reducing and Maintaining Serum Urate)
trial (92), and the open-label EXCEL (Febuxostat/
Allopurinol Comparative Extension Long-Term) study
(93). The details of these studies are presented in Table
2. More than 90% of enrolled participants were men;
mean age was approximately 52 years, and mean base-
line serum urate level was approximately 583 μmol/L
(9.8 mg/dL).
Across the studies, patients were randomly as-
signed to various doses of febuxostat (40, 80, 120,
and/or 240 mg/d; doses >80 mg/d are not FDA-
approved), allopurinol, or placebo, with adjustment for
renal insufficiency. Patients in all studies received pro-
phylaxis with colchicine or naproxen when starting
urate-lowering therapy. The findings were as follows.
First, all active therapies decreased serum urate levels
compared with placebo. Second, no important differ-
ences were seen between treatment groups or be-
tween active treatment and placebo in the frequency of
acute gout attacks. Third, in the long-term extension
study (EXCEL), patients achieving a serum urate level
less than 357 μmol/L (<6 mg/dL) had progressive de-
creases in their risk for acute gout attacks (to about 5%
at 12 months and near zero at 32 months), regardless
of choice of urate-lowering therapy. Fourth, febuxostat,
80 mg/d, was more effective than allopurinol, 300
mg/d, at decreasing serum urate levels. Fifth, no major
or important differences were seen in outcomes or total
adverse events between allopurinol, 300 mg/d, and fe-
buxostat, 40 mg/d. Sixth, discontinuation of colchicine
or naproxen prophylaxis after 8 weeks in both APEX
and FACT was associated with a spike in acute gout
attacks not seen in CONFIRMS, which maintained pro-
phylaxis throughout the 6-month duration of the study.
Finally, studies assessing comparative effectiveness in
subgroups were sparse but generally found no differ-
ences in clinical outcomes, although they had limited
power to detect such differences (3). Several smaller
studies had findings similar to those of the larger ran-
domized, controlled trials (49, 55, 63, 94, 95).
Appendix Table 3 (available at www.annals.org)
presents selected adverse events seen in the random-
ized, controlled trials of urate-lowering therapy. Differ-
ences between active treatments and between active
treatments and placebo were mostly small and not sta-
tistically significant. Although skin rash was not statisti-
cally significantly more likely in allopurinol-treated pa-
tients in these trials, observational evidence suggested
that allopurinol is a cause of DRESS (drug rash with
eosinophilia and systemic symptoms) syndrome (65,
68 –70, 72) and is more common in patients with the
HLA-B*5801 allele (41, 62, 66, 74, 79, 86, 88).
In summary, high-strength evidence suggests that
urate-lowering therapy reduces serum urate levels.
However, it does not reduce the risk for acute gout
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 Systematic Review in Support of ACP Guideline on Management of Gout REVIEW

Table 2. Key Trials of Urate-Lowering Therapy in Patients With Gout

Study, Year Study Population Average Male, Mean Participants, Comparison Duration Results
(Reference) Age, y % Baseline n
Serum
Urate
Level,
␮mol/L
(mg/dL)
APEX; Adults with gout and 52 93 583 (9.8) 1072 1. Placebo 28 wk All treatments reduced
Schumacher hyperuricemia; 2. Allopurinol, 300 mg/d serum urate levels
et al, 28% had tophi 3. Febuxostat, 80 mg/d more than placebo.
2008 (90) 4. Febuxostat, 120 mg/d Proportion of
5. Febuxostat, 240 mg/d participants
All patients were treated achieving serum
with colchicine or urate levels <357
naproxen for μmol/L (<6 mg/dL):
prophylaxis for 8 wk Allopurinol, 300
mg/d: 41%
Febuxostat, 80
mg/d: 76%
No difference in acute
gout attacks
between febuxostat,
80 mg/d, and
allopurinol,
300 mg/d.
No differences in “any
adverse event.”
FACT; Adults with gout and 52 96 583 (9.8) 760 1. Allopurinol, 300 mg/d 52 wk Proportion of
Becker et al, hyperuricemia; 2. Febuxostat, 80 mg/d participants
2005 (91) 24% had tophi 3. Febuxostat, 120 mg/d achieving serum
All patients were treated urate level <357
with colchicine or μmol/L (<6 mg/dL):
naproxen for Allopurinol, 300
prophylaxis for 8 wk mg/d: 21%
Febuxostat, 80
mg/d: 53%
No difference in acute
gout attacks
between allopurinol,
300 mg/d, and
febuxostat, 80 mg/d
(64% each).
No differences in “any
treatment related
adverse events.”
CONFIRMS; Adults with gout and 53 94 571 (9.6) 2268 1. Allopurinol, 300 mg/d 6 mo Proportion of
Becker et al, hyperuricemia (200 mg/d in patients participants
2010 (92) with renal impairment) achieving serum
2. Febuxostat, 40 mg/d urate level <357
3. Febuxostat, 80 mg/d μmol/L (<6 mg/dL):
All patients were treated Allopurinol, 300 or
with colchicine or 200 mg/d: 42%
naproxen for Febuxostat, 40
prophylaxis for 6 mo mg/d: 45%
Febuxostat, 80
mg/d: 67%
No difference in acute
gout attacks
between groups
(10%–15% at
beginning of
treatment, 5%–8% at
end of trial).
No differences
between groups in
total participants
with an adverse
event.
Continued on following page

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 REVIEW
Table 2—Continued
Study, Year Study Population Average Male,
(Reference) Age, y % Baseline
EXCEL; Open-label 51 – 583 (9.8)
Becker et al, extension trial
2009 (93) enrolling patients
from FACT and
APEX
APEX = Allopurinol- and Placebo-Controlled Efficacy Study of Febuxostat; CONFIRMS = Confirmation of Febuxostat in Reducing and Maintaining
Serum Urate; EXCEL = Febuxostat/Allopurinol Comparative Extension-Long Term; FACT = Febuxostat versus Allopurinol Controlled Trial.
attacks in the first 6 months. Long-term extension stud-
ies show that patients continuing urate-lowering ther-
apy who achieve serum urate reductions have fewer
acute gout attacks, which supports the moderate-
strength conclusion that urate-lowering therapy re-
duces the risk for such attacks after about 1 year.
Prophylaxis Against Acute Gout Attacks at
Initiation of Urate-Lowering Therapy
Initiation of therapy to decrease serum urate levels
is associated with an increased frequency of acute gout
attacks (96). This is a likely explanation for the observa-
tion that use of urate-lowering therapy does not reduce
the frequency of acute gout attacks compared with pla-
cebo for the first 6 months. More than 30 years ago,
investigators tested colchicine as prophylaxis against
acute attacks for patients starting uricosuric therapy
(97, 98). However, the first randomized, placebo-
controlled trial of colchicine prophylaxis at initiation of
allopurinol therapy was not published until 2004 (57).
In this study, investigators randomly assigned 51 pa-
tients to colchicine, 0.6 mg twice daily, or placebo
when starting allopurinol therapy at 100 mg once daily
and titrating upward, with a target serum urate level of
387 μmol/L (6.5 mg/dL). Occurrence of gout attacks
was recorded by patient recall at 3- and 6-month visits.
Among 43 patients who completed the trial (mean age,
63 years; >50% male; >60% with tophi; approximately
10% with chronic renal insufficiency), 77% of placebo
recipients versus 33% of colchicine-treated patients
had gout attacks (P = 0.008). During the first 3 months
of treatment, placebo recipients averaged about 2 at-
tacks and colchicine-treated patients averaged about
0.5 attack. From months 3 to 6, this advantage dimin-
ished, with about 1 attack per patient in the placebo
group and almost no attacks in the colchicine group.
Diarrhea was much more common in colchicine-treated
patients (43%) than in placebo recipients (approxi-
mately 4%).
The use of prophylactic therapy concomitant with
the initiation of urate-lowering therapy has been the
recommended standard of care for many years (99,
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Systematic Review in Support of ACP Guideline on Management of Gout
Mean Participants, Comparison Duration Results
n
Serum
Urate
Level,
␮mol/L
(mg/dL)
1086 1. Allopurinol, 300 mg/d 31–40 mo Maintenance of serum
(100 mg/d in patients (664 urate level <357
with renal impairment) participants μmol/L (<6 mg/dL)
(n = 145) [61%] resulted in
2. Febuxostat, 80 mg/d completed progressive
(n = 649) the study) reduction in
3. Febuxostat, 120 mg/d proportion of
(n = 292) participants with
acute gout attacks,
to near zero by
32 mo.
100). All 3 of the recent large trials of urate-lowering
therapy (FACT, APEX, and CONFIRMS) used prophy-
laxis with colchicine or NSAIDs (90 –92), even though no
randomized trials had assessed NSAIDs as a prophylac-
tic therapy for urate-lowering therapy. In both FACT
and APEX, the number of acute attacks spiked after dis-
continuation of prophylaxis at 8 weeks, with an approx-
imate doubling of the proportion of patients reporting
an attack (from 20% before to 40% after discontinua-
tion). CONFIRMS, which continued prophylaxis for the
entire 6 months of the trial, saw no spike in attacks.
One randomized trial with high risk of bias
compared different durations of colchicine prophylaxis
in patients with gout initiating allopurinol therapy (59).
However, the outcome measure was “any evidence of
recurrence of gouty arthritis,” and the criteria for this
clinical event and loss to follow-up were not
specified.
Wortmann and colleagues collected adverse event
data from all 3 of the major trials of febuxostat and
allopurinol and pooled data from FACT and APEX (56).
None of these trials randomly assigned patients to dif-
ferent prophylaxis regimens; rather, selection bias was
potentially present because assignment was at the dis-
cretion of the treating physician. In all 3 studies, upper
respiratory infection was the most frequently reported
adverse event (8% to 9% in each group, with no statis-
tically significant difference). Overall, adverse events
were higher with colchicine prophylaxis than with
naproxen prophylaxis (55% vs. 44%). Diarrhea was
about 3 times more common with colchicine than with
naproxen (8.4% vs. 2.7%). In CONFIRMS, no statistically
significant difference was seen in overall adverse
events reported (about 55% in both groups), but gas-
trointestinal and abdominal pains were about 3 times
more frequent in naproxen-treated patients (3.2% vs.
1.2%). Headache was more commonly reported in
colchicine-treated patients (2.8% vs. 0.9%).
In summary, high-strength evidence suggests that
prophylaxis with either colchicine or NSAIDs reduces
the risk for acute gout attacks in patients initiating
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 Systematic Review in Support of ACP Guideline on Management of Gout
urate-lowering therapy. The optimal duration of such
prophylactic therapy is unknown, but moderate-
strength evidence suggests that it should be longer
than 8 weeks.
Treatment Monitoring of Patients With Gout
A large body of evidence (which includes the fact
that urate is soluble up to a concentration of about 404
μmol/L [6.8 mg/dL], above which precipitation may be-
gin [101]) supports the hypothesis that lower serum
urate levels are causally associated with a lower rate of
acute gout attacks. A post hoc analysis that combined
data from 3 large trials (ULT, FACT, and APEX) pro-
vided the best clinical data about the relationship be-
tween achieved urate levels and risk for acute gout at-
tacks (102). That analysis included more than 1800
patients with gout and a baseline serum urate level of
476 μmol/L (8.0 mg/dL) or greater. The achieved urate
level was 1 of 3 variables (along with baseline presence
of tophi and percentage change in serum urate level
from baseline) that were associated with acute gout at-
tacks requiring treatment (adjusted odds ratio, 1.42
[95% CI, 1.16 to 1.73] and 2.70 [CI, 1.72 to 4.22] at 6
and 12 months after initiation of therapy, respectively).
Patients who achieved a serum urate level less than 357
μmol/L (<6.0 mg/dL) at the end of 1 year had a risk for
acute gout attacks of approximately 5%, whereas pa-
tients with levels at or above 357 μmol/L (≥6.0 mg/dL)
had risks of about 10% to 15%. Other reports, including
analyses from several retrospective cohort studies, sup-
port a relationship between achieved lower serum
urate levels and reduced risk for acute gout attacks
(103–108). One study that reported outcomes for a co-
hort of 158 patients with incident gout who were fol-
lowed for a mean of 13 years found that 70% had a
flare during the extended follow-up and that higher
urate levels were predictive of a subsequent acute flare
(odds ratio, 1.35 [CI, 1.2 to 1.5]) (109).
There are potential nonarticular impacts of hyper-
uricemia in patients with gout that may be affected by
serum urate levels. One retrospective observational
study of U.S. veterans with gout used the U.S. Depart-
ment of Veterans Affairs data warehouse to follow 2116
patients for a mean of 6.5 years. Comparing patients
with high versus low serum urate levels, the investiga-
tors reported about a 2-fold difference in new diagno-
ses of kidney disease (4% vs. 2% at year 1 and 9% vs.
5% at year 3, respectively) (110). A second study used
U.S. claims data to identify 24 108 pairs of patients with
gout who were or were not treated with urate-lowering
therapy and were followed for slightly more than a
year. Cardiovascular events were common in both
groups (incidence rates were 24% and 21%), but there
were no statistically significant differences in the com-
posite outcome or its components between groups
(111).
In summary, the only way to assess whether urate-
lowering therapy in patients with gout is having the de-
sired effect on serum urate levels is by monitoring, but
no direct evidence supports or refutes the value of such
monitoring. The notion that decreasing serum urate
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levels will reduce the risk for acute gout attacks is sup-
ported by physiology and observational evidence. The
evidence base for use of serum urate level as a target
value for treatment is limited by the lack of any trial that
has based treatment decisions on different specific tar-
gets (such as a target of 416 vs. 357 μmol/L [7.0 vs. 6.0
mg/dL]) or any target as opposed to treating symp-
toms. Treating to a target necessarily means increasing
doses of medication in patients who may be asymp-
tomatic. The value of such a strategy has yet to be
proved, and examples exist from other studies using
intermediary biomarkers (such as elevated blood pres-
sure or blood glucose level or low hemoglobin level),
in which treating to a target resulted in more adverse
effects than benefits. Thus, despite the strong biologic
appeal of such a strategy and its advocacy by major
specialty society guidelines (99, 100, 112), we judged
the strength of evidence for monitoring to be low.
Discontinuation of Pharmaceutical Management
for Patients Receiving Medications for Chronic
Gout
Three prospective observational cohort studies
found that some patients who were currently being
treated remained asymptomatic for up to 2 or 3 years
after urate-lowering therapy was stopped and that se-
rum urate levels in the presence or absence of treat-
ment were strong predictors of which patients re-
mained asymptomatic (113–115). Because a strategy of
treatment discontinuation has never been tested in a
clinical trial, we judged the strength of evidence to
be insufficient that criteria exist to identify patients
for whom urate-lowering therapy can be safely
discontinued.
DISCUSSION
A principal finding of this review is that high-
strength evidence suggests that colchicine, NSAIDs,
and corticosteroids help reduce symptoms in patients
with acute gout (Table 3). Despite the limited number
of placebo-controlled trials, we were able to reach
strong conclusions due to specific features of gout,
namely that symptoms result from an inflammatory re-
action to the deposition of urate crystals, which occurs
when the level of urate increases above its saturation
point in the blood. Hence, in an era that predated the
widespread practice of placebo-controlled trial testing
of therapies, clinicians prescribed anti-inflammatory
medications to treat symptoms of acute gout.
Corticosteroids are among the most powerful and
effective anti-inflammatory medications available. Al-
though no randomized, placebo-controlled trials have
tested their use in acute gout, corticosteroids have
proven efficacy in other inflammatory conditions, which
increases our confidence that they are effective in treat-
ing the inflammatory reaction in acute gout. With re-
gard to the management of hyperuricemia in patients
with gout, we likewise used direct and indirect evi-
dence to reach conclusions about the effectiveness of
urate-lowering therapy at reducing the risk for acute
Annals of Internal Medicine • Vol. 166 No. 1 • 3 January 2017 45
 REVIEW Systematic Review in Support of ACP Guideline on Management of Gout

Table 3. Summary of Prior Knowledge, Findings From the Systematic Review, and Strength of Evidence, by Key Question

Key Question
Acute gout treatment
Colchicine reduces pain
Low-dose colchicine is as effective as
higher-dose colchicine for reducing pain,
with fewer adverse effects
NSAIDs reduce gout pain
No difference between NSAIDs in effectiveness
Systemic corticosteroids reduce pain
Animal-derived corticotropin formulation
reduces pain
Prior Knowledge Used in Determining
Strength of Evidence
NA
NA
Biologic rationale (anti-inflammatory action)
Placebo-controlled RCT evidence that
NSAIDs provide temporary pain relief for
many conditions
Equivalence in effectiveness among NSAIDs
in many other conditions
Biologic rationale (anti-inflammatory action)
Biologic rationale (anti-inflammatory action)
Sources of Evidence Included in This Strength of
Systematic Review Evidence
2 placebo-controlled RCTs (n = 45 and High
184), both with low risk of bias
1 head-to-head RCT with low risk of Moderate
bias (n = 184)
1 placebo-controlled RCT with high risk High
of bias (n = 30)
High-strength observational data
(NSAID use as prophylaxis against
gout flare; see “Management of
hyperuricemia in patients with gout”
section in this table)
16 head-to-head RCTs Moderate
No placebo-controlled RCTs High
Equivalence to NSAIDs in 6 RCTs (n =
27, 90, 120, 60, 95, and 416); 4 of 6
RCTs had low risk of bias
No placebo-controlled RCTs Moderate
Approximate equivalence to NSAIDs
and intramuscular corticosteroids in
RCTs (1 RCT of each, n = 76 and 31,
both with high risk of bias)

Management of hyperuricemia in patients

with gout
ULT does not reduce the risk for acute gout
attacks within the first 6 mo
ULT reduces serum urate levels
ULT reduces the risk for acute gout attacks
after 1 y
Prophylactic therapy with low-dose colchicine
or low-dose NSAIDs reduces the risk for
acute gout attacks in patients initiating ULT
Longer durations of prophylaxis with colchicine
or NSAIDs (>8 wk) are more effective than
shorter durations in patients initiating ULT
NA 2 placebo-controlled RCTs with low risk High
of bias (n = 1072 and 57)
NA 4 placebo-controlled RCTs, all with low High
risk of bias (n = 1072, 96, 153,
and 57)
Acute gout attacks are caused by elevated No placebo-controlled RCTs assess Moderate
serum urate concentrations long-term risk for acute gout attacks
RCTs with low risk of bias show that ULT
reduces serum urate levels
Open-label extension study of a ULT
RCT shows reduced risk for acute
gout attacks over time (<5% at
approximately 1 y)
NA 1 placebo-controlled RCT of colchicine High
with low risk of bias (n = 43)
Strong observational evidence across 3
RCTs with low risk of bias that
included different durations of
prophylaxis (n = 762, 2269, and
1072)
NA Indirect evidence from comparisons Moderate
across 3 RCTs of differing durations
of prophylaxis
1 RCT with high risk of bias (n = 190)

Treatment monitoring
Monitoring serum urate levels improves NA No direct evidence Insufficient
outcomes An argument can be made indirectly on
the basis of the evidence that
elevated serum urate levels cause
gout
Treating to a specific target serum urate level Lower serum urate levels are associated No RCT evidence Low
reduces the risk for gout attacks with reduced risk for gout attacks Variable targets proposed or assessed
in the literature
NA = not applicable; NSAID = nonsteroidal anti-inflammatory drug; RCT = randomized, controlled trial; ULT = urate-lowering therapy.

gout attacks over time, despite the fact that this out-
come has not been studied in any placebo-controlled
trial lasting longer than a few months (Table 3). We
based our rating of moderate strength of evidence on
the high-strength evidence that urate-lowering therapy
reduces serum urate levels, that serum urate level is a
46 Annals of Internal Medicine • Vol. 166 No. 1 • 3 January 2017
strong predictor of risk for acute gout attacks, and that
the open-label extension studies of urate-lowering
therapy trials have shown a graded relationship be-
tween the serum urate level achieved and the risk for
acute gout attacks. We concluded that after the initial
period of increased risk for acute gout attacks associ-
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 Systematic Review in Support of ACP Guideline on Management of Gout
ated with initiation of urate-lowering therapy, such ther-
apy reduces the risk for acute attacks. The increased
risk during the initial period can be reduced with con-
current use of anti-inflammatory prophylaxis.
Our review reached stronger strength-of-evidence
ratings than some prior reviews, particularly Cochrane
reviews, that concluded that the strength of evidence is
“inconclusive” with regard to corticosteroids (116),
“low-quality” with regard to colchicine (117), “limited”
with regard to NSAIDs (118), and “low-moderate” with
regard to allopurinol (44). Non-Cochrane reviews
tended to reach stronger conclusions (for example, “all
therapies were found to be effective” [119]).
The most important question to be answered for
the treatment of gout in primary care is whether using
urate-lowering therapy to treat all patients to a specific
goal, such as less than 357 μmol/L (<6.0 mg/dL), im-
proves patient outcomes. This concept of “treat-to-
target” is supported by indirect evidence but has not
been tested. Guidelines and recommendations about
treatment target thresholds vary; for example, less than
357 μmol/L (<6.0 mg/dL) is the most commonly sug-
gested threshold, but recent American College of
Rheumatology guidelines suggest a threshold of less
than 297 μmol/L (<5.0 mg/dL) for some patients “to
improve signs and symptoms of gout” (100). However,
for many patients whose gout is clinically well-
controlled (no flares) during urate-lowering therapy, no
direct data support such targets. In fact, the results of
one cohort study suggest that once gout has been
asymptomatic for 5 years, urate-lowering therapy might
be discontinued for many years as long as serum urate
levels remain acceptable (for example, <416 μmol/L
[<7 mg/dL]) (114).
Our review identified several limitations beyond
the lack of placebo-controlled studies. For many of the
questions of interest, data were not reported on the
subgroups or outcomes of interest. Only 10 studies ex-
plicitly stated that patients came exclusively from pri-
mary care sites or included such patients. We thus
judged this evidence to be moderately applicable to
primary care.
In summary, use of colchicine, NSAIDs, and cortico-
steroids to relieve symptoms of acute gout attacks is
supported by high-strength evidence. In addition, high-
strength evidence suggests that urate-lowering therapy
with allopurinol or febuxostat decreases serum urate
levels, and moderate-strength evidence shows that it
reduces the risk for acute gout attacks after several
months. In patients initiating urate-lowering therapy,
high-strength evidence supports use of prophylactic
colchicine or NSAIDs for more than 8 weeks to reduce
the risk for acute gout attacks. Use of a treat-to-target
strategy for patients with gout and hyperuricemia has
logical appeal and is supported by observational evi-
dence but has not been experimentally tested. A long-
term trial of a treat-to-target strategy is the most impor-
tant research need for the management of gout in
primary care.
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REVIEW
From RAND Corporation, Santa Monica, and Veterans Affairs
Greater Los Angeles Healthcare System and David Geffen
School of Medicine at the University of California, Los Ange-
les, Los Angeles, California.
Disclaimer: The authors of this manuscript are responsible for
its content. Statements in the manuscript should not be con-
strued as endorsement by the Agency for Healthcare Re-
search and Quality (AHRQ) or the U.S. Department of Health
and Human Services. AHRQ retains a license to display, repro-
duce, and distribute the data and the report from which this
manuscript was derived under the terms of the agency's con-
tract with the author.
Acknowledgment: The authors thank Patricia Smith for her
administrative assistance on the project and acknowledge the
guidance provided by the key informants and technical expert
panel members on the evidence report.
Financial Support: This project was funded under contract
290-2012-00006I from the AHRQ, U.S. Department of Health
and Human Services.
Disclosures: All authors report a grant from AHRQ during the
conduct of the study. Dr. Shekelle reports personal fees from
ECRI Institute outside the submitted work and royalties from
UpToDate. Authors not named here have disclosed no other
conflicts of interest. Disclosures can also be viewed at www
.acponline.org/authors/icmje/ConflictOfInterestForms.do
?msNum=M16-0461.
Reproducible Research Statement: Study protocol: Available
at http://effectivehealthcare.ahrq.gov/ehc/products/564/1992
/Gout-managment-protocol-141103.pdf. Statistical code: Not
applicable. Data set: Available in the full report at https://
effectivehealthcare.ahrq.gov/search-for-guides-reviews-and-
reports/?pageaction=displayproduct&productID=2195.
Requests for Single Reprints: Paul G. Shekelle, MD, PhD,
RAND Corporation, 1776 Main Street, Santa Monica, CA
90401; e-mail, shekelle@rand.org.
Current author addresses and author contributions are avail-
able at www.annals.org.
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Database Syst Rev. 2008:CD005521. [PMID: 18425920] doi:10
.1002/14651858.CD005521.pub2
117. van Echteld I, Wechalekar MD, Schlesinger N, Buchbinder R,
Aletaha D. Colchicine for acute gout. Cochrane Database Syst Rev.
2014:CD006190. [PMID: 25123076] doi:10.1002/14651858.
CD006190.pub2
118. van Durme CM, Wechalekar MD, Buchbinder R, Schlesinger N,
van der Heijde D, Landewé RB. Non-steroidal anti-inflammatory
drugs for acute gout. Cochrane Database Syst Rev. 2014:CD010120.
[PMID: 25225849] doi:10.1002/14651858.CD010120.pub2
119. Khanna PP, Gladue HS, Singh MK, FitzGerald JD, Bae S,
Prakash S, et al. Treatment of acute gout: a systematic review. Semin
Arthritis Rheum. 2014;44:31-8. [PMID: 24650777] doi:10.1016/j
.semarthrit.2014.02.003
Annals of Internal Medicine • Vol. 166 No. 1 • 3 January 2017 51
 Current Author Addresses: Drs. Shekelle and Newberry, Ms.
Motala, Ms. O’Hanlon, Mr. Tariq, Ms. Han, and Ms. Shanman:
RAND Corporation, 1776 Main Street, Santa Monica, CA
90401.
Dr. FitzGerald: David Geffen School of Medicine at the Uni-
versity of California, Los Angeles, Rehabilitation Center, Room
32-59, 1000 Veteran Avenue, Los Angeles, CA 90095.
Dr. Okunogbe: RAND Corporation, 1200 South Hayes Street,
Arlington, VA 22202.
www.annals.org
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Author Contributions: Conception and design: P.G. Shekelle.
Analysis and interpretation of the data: P.G. Shekelle, S.J.
Newberry, J.D. FitzGerald, C.E. O’Hanlon, A. Tariq, A.
Okunogbe, D. Han.
Drafting of the article: P.G. Shekelle, S.J. Newberry, J.D.
FitzGerald, A. Motala, A. Tariq, A. Okunogbe.
Critical revision of the article for important intellectual con-
tent: P.G. Shekelle, S.J. Newberry, J.D. FitzGerald, C.E.
O’Hanlon, A. Okunogbe.
Final approval of the article: P.G. Shekelle, S.J. Newberry, J.D.
FitzGerald, A. Motala, C.E. O’Hanlon, A. Tariq, A. Okunogbe,
D. Han, R. Shanman.
Obtaining of funding: P.G. Shekelle.
Administrative, technical, or logistic support: A. Motala.
Collection and assembly of data: P.G. Shekelle, A. Motala,
C.E. O’Hanlon, A. Tariq, A. Okunogbe, D. Han, R. Shanman.
Annals of Internal Medicine • Vol. 166 No. 1 • 3 January 2017
 Appendix Table 1. Detailed Search Methods

Database searched and time period covered

PubMed—1/1/2010-3/1/2016
Search strategy:
"Gout"[Mesh] OR gout[tiab] OR gouty[tiab] OR toph*

Database searched and time period covered

PubMed—1/1/2010-3/1/2016
Search strategy:
Gout suppressants[mh]
NOT
"Gout"[Mesh] OR gout[tiab] OR gouty[tiab] OR toph*

Database searched and time period covered

Embase—1/1/2010-3/1/2016
Search strategy:
gout:de,ab,ti OR gouty:de,ab,ti OR toph*:de,ab,ti
AND
[humans]/lim
AND
[embase]/lim

Database searched and time period covered

Web of Science Indexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S,
CPCI-SSH—1/1/2010-3/1/2016
Search strategy:
TS=(gout OR gouty OR toph*)
NOT
ts=(Aicardi-Goutieres)

Database searched and time period covered

Cochrane Databases—1/1/2010-3/1/2016
Search strategy:
'gout OR gouty OR toph* in Title, Abstract, Keywords

Forward searches on the following article

Zhang W, Doherty M, Bardin T, Pascual E, Barskova V, Conaghan P,
et al; EULAR Standing Committee for International Clinical Studies
Including Therapeutics. EULAR evidence based recommendations
for gout. Part II: management. Report of a task force of the EULAR
Standing Committee for International Clinical Studies Including
Therapeutics (ESCISIT). Ann Rheum Dis. 2006;65:1312-24. [PMID:
16707532]

Database searched and time period covered

Web of Science—1/1/2010-3/1/2016
Search strategy:
CITED AUTHOR: (zhang w*) AND CITED WORK: (ann rheum dis)
AND CITED YEAR: (2006)

Database searched and time period covered

SCOPUS—1/1/2010-3/1/2016
Search strategy:
AUTHOR-NAME(zhang w*) AND TITLE-ABS-KEY(gout) AND
PUBYEAR > 2005
Select citations to this article

Database searched and time period covered

ClinicalTrials.gov—Earliest-3/1/2016
Search strategy:
CONDITION = "Gout"

Manual filtering in endnote to remove duplicates, animal-only

studies, “GOUT” as French for “TASTE,” “TOPHAT” (re:
GENETICS), historical account, authors named “GOUT” OR
“TOPH*

ClinicalTrials.gov
CONDITION = "Gout"
RECEIVED FROM: Earliest in database to 3/1/2016

Annals of Internal Medicine • Vol. 166 No. 1 • 3 January 2017 www.annals.org

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 Appendix Table 2. Randomized, Controlled Trials of NSAID Versus NSAID for Treatment of Acute Gout

Study, Year Sample NSAID 1 Dose 1 NSAID 2 Dose 2 Statistically or

(Reference) Size, n Clinically Important
Differences in
Effectiveness
Douglas and Thompson, 25 Flufenamic acid 800 mg/d for 4 d, Phenylbutazone 800 mg/d for 4 d, No
1970 (28) then 400 mg/d then 400 mg/d
Siegmeth and Placheta, 46 Ketoprofen 50 mg BID Phenylbutazone 300 mg BID No
1976 (32)
Ruotsi and Vainio, 18 Proquazone 300 mg TID, then Indomethacin 50 mg TID, then No
1978 (19) 300 mg QD 50 mg QD
Weiner et al, 1979 (27) 30 Fenoprofen 3.6 g day 1, then Phenylbutazone 700 mg day 1, No
3.0 g days 2–4 then 400 mg
days 2–4
Eberl and Dunky, 20 Meclofenamate 800 mg/d, then Indomethacin 200 mg/d, then No
1983 (18) 100 mg TID 50 mg TID
Butler et al, 1985 (29) 33 Flurbiprofen 400 mg/d for 2d, Phenylbutazone 800 mg/d for 2d, No
then 200 mg/d 400 mg/d
Lomen et al, 1986 (31) 29 Flurbiprofen 400 mg/d for 1 d, Indomethacin 200 mg/d for 1 d, No
then 200 mg/d then 100 mg/d
Altman et al, 1988 (17) 59 Ketoprofen 100 mg TID Indomethacin 50 mg TID No
Lederman, 1990 (21) 60 Etodolac 300 mg BID Naproxen 500 mg TID No
Maccagno et al, 1991 (8) 61 Etodolac 300 mg BID Naproxen 500 mg BID No
Shrestha et al, 1995 (16) 20 Ketorolac 60 mg once Indomethacin 50 mg once No
Schumacher et al, 150 Etoricoxib 120 mg QD for Indomethacin 50 mg TID for 8 d No
2002 (22) 8d
Cheng et al, 2004 (15) 62 Rofecoxib 50 mg Diclofenac 150 mg Rofecoxib equivalent to
NSAID 3: 15 mg diclofenac
Meloxicam Rofecoxib superior to
meloxicam
Meloxicam equivalent
to diclofenac
Rubin et al, 2004 (23) 189 Etoricoxib 120 mg QD Indomethacin 50 mg TID No
Schumacher et al, 400 Celecoxib 50 mg BID, Indomethacin 50 mg TID High-dose celecoxib
2012 (9) 200 mg BID, equivalent to
400 mg BID indomethacin
Low-dose celecoxib
inferior to
indomethacin
Li et al, 2013 (11) 78 Etoricoxib 120 mg/d Indomethacin 75 mg BID No
BID = twice daily; NSAID = nonsteroidal anti-inflammatory drug; QD = once daily; TID = 3 times daily.

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 Appendix Table 3. Adverse Events of Urate-Lowering Therapy From Selected Randomized, Controlled Trials*

Study, Year (Reference) Placebo Allopurinol, Febuxostat, Febuxostat,

300 mg/d 40 mg/d 80 mg/d
APEX; Schumacher et al, 2008 (90)
Any adverse event 97/134 (72) 200/268 (75) – 181/267 (68)
Serious adverse events 2/134 (1) 7/268 (3) – 11/267 (4)
Diarrhea 11/134 (11) 17/268 (6) – 16/267 (6)
Hypertension 8/134 (6) 3/268 (1) – 13/267 (5)
Muscle cramps/twitching 7/134 (5) 1/268 (1) – 3/267 (1)
ALT level >1.5 times ULN 19/129 (15) 52/262 (20) – 64/258 (25)
AST level >1.5 times ULN 19/129 (11) 33/262 (13) – 49/258 (19)

FACT; Becker et al, 2005 (91)

Any treatment-emergent event – 189/253 (75) – 205/256 (80)
Any serious adverse event – 19/253 (8) – 11/256 (4)
Diarrhea – 8/253 (3) – 8/256 (3)
LFT abnormalities – 11/253 (4) – 9/256 (4)
Musculoskeletal symptoms – 5/253 (2) – 5/256 (2)

CONFIRMS; Becker et al, 2010 (92)

Any adverse event – 433/756 (57) 129/757 (57) 410/756 (54)
Any serious adverse event – 19/756 (2) 31/756 (4) 28/756 (4)
Liver function “analysis” – 50/756 (7) 63/757 (8) 52/756 (7)
Diarrhea – 57/756 (8) 45/757 (6) 42/756 (6)
Rash – 55/756 (7) 44/757 (6) 42/756 (6)
Musculoskeletal signs and symptoms – 32/756 (4) 43/757 (6) 30/756 (5)

Huang et al, 2014 (55)

Any adverse event – 103/172 (60) 96/172 (56) 89/172 (52)
Any serious adverse event – 2/172 (1) 2/172 (1) 2/172 (1)
LFT abnormalities – 6/172 (3) 5/172 (3) 2/172 (1)

Becker et al, 2005 (95)

Abdominal pain 5/38 (13) – 3/37 (8) 3/40 (8)
Diarrhea 8/38 (21) – 0/37 (0) 10/40 (25)
LFT abnormalities 0/38 (0) – 5/37 (14) 3/40 (8)

Saag et al, 2013 (49)†

Elevated serum creatinine level 17/32 (53) – – 16/32 (50)
ALT = alanine aminotransferase; APEX = Allopurinol- and Placebo-Controlled Efficacy Study of Febuxostat; AST = aspartate aminotransferase;
CONFIRMS = Confirmation of Febuxostat in Reducing and Maintaining Serum Urate; FACT = Febuxostat versus Allopurinol Controlled Trial; LFT =
liver function test; ULN = upper limit of normal.
* Values are numbers of events/patients (percentages).
† Patients received febuxostat, 40 mg/d, titrated up to 80 mg/d to achieve a serum urate level <357 μmol/L (<6 mg/dL).

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