Gout, a common form
of inflammatory arthritis, is characterized by acute intermittent episodes of
synovitis that cause joint swelling and pain. Approximately 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 frequent, protracted, and severe and may progress to a chronic
inflammatory condition. In addition, some patients develop tophi, which are
deposits of urate crystals at the surface of joints or in skin or cartilage.
This systematic review was proposed by the American College of Physicians (ACP)
to support the development of a clinical practice guideline that would aid
primary care practitioners in the management of adult patients with gout.
Methods We developed a protocol ); followed PRISMA (Preferred Reporting Items
for Systematic reviews and Meta-Analyses) guidelines for reporting systematic
reviews (2); and detailed 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 questions 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
monitoring of serum urate levels and whether criteria exist to identify
patients who are candidates for discontinuation 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 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
references were obtained from 29 recent systematic reviews. 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 manufacturers of
prescription medications used to treat gout for recently completed studies and
unpublished or nonpeer-reviewed study findings in July 2014. Appendix Table 1
provides detailed search methods. Appendix Table 1. Detailed Search Methods
Study Selection Two reviewers independently screened records (titles, abstracts,
and articles) to identify reviews and studies that reported on the benefits
(randomized trials) or harms (observational studies and trials) of treatment
and management strategies for gout. We examined 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 formal gout diagnosis (based on either
synovial fluid analysis or a clinical diagnosis) were excluded. Data Extraction
and Quality Assessment Study-level details were abstracted by one reviewer and
checked by a second reviewer, with reconciliation 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, moderate, low, or insufficient for each
conclusion by using guidance suggested by the Effective Health Care Program
(6). We also applied criteria proposed by Bradford Hill for causality when
judging strength of evidence (7), including the strength, consistency, and
specificity of the association; the temporal relationship; the biologic
gradient or doseresponse curve; the biologic 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 reviewed the draft
report. Results The Figure shows the search and selection process that
identified 155 articles meeting the inclusion criteria. Of these, 22 evaluated
dietary therapy or traditional Chinese medicine; details about the inconclusive
evidence from those studies are in the evidence report (3). Figure. Literature flow
diagram. * 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).
Pharmacologic Treatment for Acute Gout We identified evidence for several
pharmacologic treatments for acute gout: colchicine, NSAIDs, corticosteroids,
and animal-derived corticotropin formulation (835). 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 College 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 relief 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% reduction 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 better tolerated; for example,
23% versus 77% of patients receiving low- and high-dose therapy reported
diarrhea, and 0% versus 19% of these patients reported severe diarrhea (Table
1). Table 1. Key Trials of Treatments for Acute Gout 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 proportion 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, 1519, 2123, 2729,
31, 32). Most studies found no statistically significant differences 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
power to detect differences (Appendix Table 2). Appendix Table 2. Randomized,
Controlled Trials of NSAID Versus NSAID for Treatment of Acute Gout
Corticosteroids No published placebo-controlled trials assessed oral corticosteroids
for acute gout. Six randomized trials compared corticosteroids (3 oral, 2
intramuscular, and 1 intravenous) versus NSAIDs. These studies, which enrolled
27 (20), 60 (13), 90 (24), 92 (33), 120 (10), and 416 (34) patients, found few
differences in effectiveness or adverse events between treatments. In one study
of oral corticosteroids, 90 patients presenting to the emergency department
with acute arthritis suggestive of gout were randomly assigned to receive
either prednisolone, 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; all patients also received
paracetamol. No statistically or clinically significant between-group
differences were seen at any evaluation point (up to 14 days). More patients in
the indomethacin group than the prednisolone 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 differences in effectiveness outcomes were
observed between groups. Equal proportions of patients in both groups reported
an adverse event (66% vs. 63%) (10). The third study of oral corticosteroids
randomly assigned 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.