Management of Gout: A Systematic Review in Support of an American College of Physicians Clinical Practice Guideline

Paul G. Shekelle; Sydne J. Newberry; John D. FitzGerald; Aneesa Motala; Claire E. O'Hanlon; Abdul Tariq; Adeyemi Okunogbe; Dan Han; Roberta Shanman

doi:10.7326/M16-0461

Reviews |3 January 2017

Management of Gout: A Systematic Review in Support of an American College of Physicians Clinical Practice Guideline Free

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; Roberta Shanman, MLS

Paul G. Shekelle, MD, PhD

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 Angeles, Los Angeles, California.

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

Roberta Shanman, MLS

Article, Author, and Disclosure Information

This article was published at www.annals.org on 1 November 2016.

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 Angeles, Los Angeles, California.
Disclaimer: The authors of this manuscript are responsible for its content. Statements in the manuscript should not be construed as endorsement by the Agency for Healthcare Research and Quality (AHRQ) or the U.S. Department of Health and Human Services. AHRQ retains a license to display, reproduce, and distribute the data and the report from which this manuscript was derived under the terms of the agency's contract 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.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
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: 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 University 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.
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 content: 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.

Abstract

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 attacks, management of hyperuricemia to prevent attacks, and discontinuation 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 reviewer and checked by a second reviewer. Study quality was assessed by 2 independent reviewers. Strength-of-evidence assessment was done by group discussion.

Data Synthesis:

High-strength evidence from 28 trials (only 3 of which were placebo-controlled) shows that colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids reduce pain in patients with acute gout. Moderate-strength evidence suggests that low-dose colchicine is as effective as high-dose colchicine and causes fewer gastrointestinal adverse 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 evidence indicates that duration of prophylaxis should be longer than 8 weeks. Although lower urate levels reduce risk for recurrent 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)

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 (http://effectivehealthcare.ahrq.gov/ehc/products/564/1992/Gout-managment-protocol-141103.pdf); 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 non–peer-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 dose–response 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 (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 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, 15–19, 21–23, 27–29, 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. 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 corticotropin 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 intramuscularly 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 corticotropin 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 reported gastrointestinal adverse events (no adverse events were reported by patients receiving corticotropin) (Table 1).

Summary

Despite the small number of placebo-controlled trials, we judged the strength of evidence as high that colchicine, NSAIDs, and corticosteroids relieve pain in patients with acute gout, based on the known physiology 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 corticotropin 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 reviews, 9 new trials assessing effectiveness (55–63), and 26 studies of adverse effects that addressed this question (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 baseline serum urate level was approximately 583 µmol/L (9.8 mg/dL).

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

Across the studies, patients were randomly assigned 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 prophylaxis 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 differences were seen between treatment groups or between 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 decreases 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 febuxostat, 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 prophylaxis throughout the 6-month duration of the study. Finally, studies assessing comparative effectiveness in subgroups were sparse but generally found no differences in clinical outcomes, although they had limited power to detect such differences (3). Several smaller studies had findings similar to those of the larger randomized, controlled trials (49, 55, 63, 94, 95).

Appendix Table 3 presents selected adverse events seen in the randomized, controlled trials of urate-lowering therapy. Differences between active treatments and between active treatments and placebo were mostly small and not statistically significant. Although skin rash was not statistically significantly more likely in allopurinol-treated patients 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).

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

In summary, high-strength evidence suggests that urate-lowering therapy reduces serum urate levels. However, it does not reduce the risk for acute gout attacks in the first 6 months. Long-term extension studies show that patients continuing urate-lowering therapy who achieve serum urate reductions have fewer acute gout attacks, which supports the moderate-strength conclusion that urate-lowering therapy reduces 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 observation that use of urate-lowering therapy does not reduce the frequency of acute gout attacks compared with placebo 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 patients 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 attacks and colchicine-treated patients averaged about 0.5 attack. From months 3 to 6, this advantage diminished, 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 (approximately 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, 100). All 3 of the recent large trials of urate-lowering therapy (FACT, APEX, and CONFIRMS) used prophylaxis with colchicine or NSAIDs (90–92), even though no randomized trials had assessed NSAIDs as a prophylactic therapy for urate-lowering therapy. In both FACT and APEX, the number of acute attacks spiked after discontinuation of prophylaxis at 8 weeks, with an approximate doubling of the proportion of patients reporting an attack (from 20% before to 40% after discontinuation). 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 different prophylaxis regimens; rather, selection bias was potentially present because assignment was at the discretion 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 statistically 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 gastrointestinal 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 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 begin [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) provided the best clinical data about the relationship between achieved urate levels and risk for acute gout attacks (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 attacks 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 patients 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, support a relationship between achieved lower serum urate levels and reduced risk for acute gout attacks (103–108). One study that reported outcomes for a cohort of 158 patients with incident gout who were followed 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 hyperuricemia 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. Department 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 investigators reported about a 2-fold difference in new diagnoses 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 composite 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 desired 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 levels will reduce the risk for acute gout attacks is supported 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 targets (such as a target of 416 vs. 357 µmol/L [7.0 vs. 6.0 mg/dL]) or any target as opposed to treating symptoms. Treating to a target necessarily means increasing doses of medication in patients who may be asymptomatic. The value of such a strategy has yet to be proved, and examples exist from other studies using intermediary biomarkers (such as elevated blood pressure 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 serum urate levels in the presence or absence of treatment were strong predictors of which patients remained 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 reaction 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.

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

Corticosteroids are among the most powerful and effective anti-inflammatory medications available. Although 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 treating the inflammatory reaction in acute gout. With regard to the management of hyperuricemia in patients with gout, we likewise used direct and indirect evidence to reach conclusions about the effectiveness of urate-lowering therapy at reducing the risk for acute gout attacks over time, despite the fact that this outcome 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 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 between 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 associated with initiation of urate-lowering therapy, such therapy reduces the risk for acute attacks. The increased risk during the initial period can be reduced with concurrent 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), improves 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 suggested 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 explicitly stated that patients came exclusively from primary 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 corticosteroids 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 evidence but has not been experimentally tested. A long-term trial of a treat-to-target strategy is the most important research need for the management of gout in primary care.

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This article was published at www.annals.org on 1 November 2016.

Appendix Table 1. Detailed Search Methods

Table 1. Key Trials of Treatments for Acute Gout

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

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

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

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

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Reviews |3 January 2017

Management of Gout: A Systematic Review in Support of an American College of Physicians Clinical Practice Guideline Free

Abstract

Methods

Key Questions

Data Sources and Searches

Appendix Table 1. Detailed Search Methods

Study Selection

Data Extraction and Quality Assessment

Data Synthesis and Grading

Role of the Funding Source

Results

Figure.

Pharmacologic Treatment for Acute Gout

Colchicine

Table 1. Key Trials of Treatments for Acute Gout

NSAIDs

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

Corticosteroids

Corticotropin

Summary

Pharmacologic Management of Hyperuricemia in Patients With Gout

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

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

Prophylaxis Against Acute Gout Attacks at Initiation of Urate-Lowering Therapy

Treatment Monitoring of Patients With Gout

Discontinuation of Pharmaceutical Management for Patients Receiving Medications for Chronic Gout

Discussion

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

References

Figure.

Appendix Table 1. Detailed Search Methods

Table 1. Key Trials of Treatments for Acute Gout

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

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

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

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

Clinical Slide Sets

This feature is available only to Registered Users

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