Skip Navigation
AHRQ--Agency for Healthcare Research and Quality: Advancing Excellence in Health Care
  • Home
  • Search for Research Summaries, Reviews, and Reports
 
 

Executive Summary – Mar. 15, 2016

Management of Gout

Formats

Table of Contents

Background and Objectives

Gout is the most common form of inflammatory arthritis and is characterized by acute intermittent episodes of synovitis presenting with joint swelling and pain (referred to as acute gouty arthritis, or acute gout attacks, or acute gout flares). It has been described as a disease of the foot since antiquity.1 Approximately 8 million patients in the United States have gout. Gout is caused when excess urate in the body crystalizes (as monosodium urate [MSU]) in joint fluid, cartilage, bones, tendons, bursas or other sites. These crystals can directly stimulate an acute inflammatory attack. In some patients, acute gout attacks become progressively more frequent, protracted, and severe and may eventually progress to a chronic inflammatory condition. Additionally, in some patients the deposits of urate crystals grow into larger collections, called tophi (singular tophus) when clinically apparent.

The aim of this report is to review the evidence for the treatment of patients with gout, focusing on the primary care setting.

Etiology of Gout

Gout initially presents as an episode of acute inflammatory arthritis, most commonly involving the first meta-tarsal-phalanx joint, a condition commonly referred to as podagra. Typical attacks during the first few years last 7 to 14 days before resolving.

Although the primary risk factor for gout is hyperuricemia, not all patients with hyperuricemia go on to develop clinical gout; hyperuricemia that does not progress to gout is known as asymptomatic hyperuricemia. Patients with asymptomatic hyperuricemia may or may not have evidence of urate deposits in their joints (as documented by advanced imaging methods).2

The causes of gout are unclear but appear to be multifactorial, including a combination of genetic, hormonal, metabolic, and dietary factors. Family history, advancing age, male sex, or, in women, early menopause have been associated with a higher risk of gout and/or gout attacks (flares).3 Some prescription medications such as thiazides are also believed to be risk factors for gout.

Diagnosis of Gout

A number of methods have been proposed to establish the diagnosis of gout. The evidence supporting the various methods for the diagnosis of gout is the subject of a separate systematic review.4

Clinical Presentation and Management

Gout encompasses both acute and chronic phases.

Acute Gouty Arthritis

The acute phase of gout is self-limited and characterized by recurrent attacks of synovitis (articular inflammation) that present with pain, erythema, and swelling, most frequently in the large toe but other joints, tendons, bursae or other areas may be involved.

Primary treatments for acute gout attacks have included non-steroidal anti-inflammatory agents (NSAIDs), corticosteroids (intraarticular), colchicine, and pituitary adrenocorticotropic hormone (ACTH, specifically animal-derived ACTH preparation) for the control of pain and inflammation.

Chronic Gout

Although initial episodes may be brief and rare, acute episodes may increase in frequency and duration over time and lead to the development of chronic gout. In addition to more frequent attacks, chronic gout may be associated with deposits of uric acid crystals known as tophi. Tophi may develop in joints, cartilage, bone, and auricular or other cutaneous tissues.5 The average interval between the onset of gout and appearance of tophi, in the absence of treatment, is approximately 10 years.5

Management of chronic gout may include both pharmacologic and non-pharmacologic strategies. Historically, the treatment of chronic gout began with identification of patients as "overproducers" or "underexcretors" of uric acid, based on 24-hour urine collection. "Overproducers" were treated preferentially with allopurinol, whereas "underexcretors" were treated preferentially with the uricosuric probenecid. However, uricosuric agents may increase the risk of renal stones, requiring increased fluid intake and alkalinization for prevention. Probenecid use has fallen out of favor, because allopurinol was found to be effective in "underexcretors".6,7 Urate lowering strategies are the primary pharmacologic intervention for management of long-term complications of gout.

Lifestyle Changes

Non-pharmacologic methods advocated for management of chronic gout include a combination of lifestyle changes, including weight loss, exercise, hydration, and dietary changes. Such changes include reduction of dietary purines and alcohol intake, based on observational studies assessing associations between dietary components and risk for gout or trials assessing the effect of specific foods or supplements on serum uric acid levels. Dietary risk factors for gout have been postulated to include alcohol consumption, as well as consumption of meat, seafood, sugar-sweetened soft drinks, and foods high in fructose, whereas dairy foods and coffee have been associated with a lower risk of incident gout and in some cases a lower rate of gout attacks (flares). The evidence for the efficacy of specific dietary changes in managing gout (preventing attacks) is a topic of this review.

Pharmacologic Agents

Pharmacologic management of chronic gout consists primarily of agents that lower serum urate. These agents include xanthine oxidase inhibitors (XOIs- allopurinol and febuxostat) to reduce serum urate production; uricosurics (probenecid), which prevent renal reabsorption of uric acid (and increase urinary uric acid excretion); and uricases, which stimulate the breakdown of uric acid (pegloticase). These agents can be used alone or in specific combinations (e.g., XOI plus probenecid). Pegloticase will not be included in this review because it would not be prescribed in a primary care setting (see below).

Table A lists the drugs used to treat gout and notes the ones covered in this systematic review.

Several interleukin-1ß-inhibitory anti-inflammatory agents currently approved for treatment of rheumatoid arthritis are in Phase II and III trials for treatment of gout, including anakinra, canakinumab, and rilonacept,8-10 and will not be included in this systematic review, because they are not prescribed in the primary care setting (see below). These treatments do not act by lowering serum urate levels.

Additional off-label agents that have been proposed as useful in the management of gout include the lipid lowering agent, fenofibrate; the angiotensin 2 receptor blocker, losartan; estrogen; and calcium channel blockers (in patients being treated with these agents for other indications). These agents are not included in this review.

Scope and Key Questions

Scope of the Review

The purpose of this review is to assess the evidence on the management of patients with gout, in both the acute and chronic phases, including patients with tophaceous gout, and to assess management therapies that are FDA-approved and within the scope of practice of typical primary care providers. A protocol for the review was accepted and publicly posted on the Effective Health Care Web site on November 3, 2014.

Key Questions

The Key Questions (KQs) that guided this review are based on questions posed by the American College of Physicians (ACP). These questions underwent revision based on input from a group of key informants, public comments, and input from a Technical Expert Panel (TEP).

Key Question 1: Acute Gout Treatment
  1. In patients with acute gout, what are the benefits and harms of different pharmacological therapies?
  2. Does effectiveness (benefits and harms) differ according to patient baseline demographic characteristics and co-morbid conditions (including renal function)?
  3. Does effectiveness (benefits and harms) differ according to disease severity, including initial clinical presentation (e.g., extent of joint involvement and time since start of flare) and laboratory values (serum and/or urine UA levels)?
Key Question 2: Dietary and Lifestyle Management of Gout
  1. In adults with gout, what are the benefits and harms of different dietary therapies and life style measures on intermediate (serum and/or urine UA levels) and final health outcomes (including recurrence of gout episodes and progression [e.g., development of tophi])?
  2. Does effectiveness and comparative effectiveness of dietary modification differ according to disease severity (including presence of tophi and baseline serum UA), underlying mechanisms of hyperuricemia, or baseline demographic and co-morbid characteristics?
Key Question 3: Pharmacologic Management of Hyperuricemia in Gout Patients
  1. In adults with gout, what are the benefits and harms of different pharmacological therapies on intermediate (serum and/or urine UA levels) and long-term clinical health outcomes (including recurrence of gout episodes and progression)?
  2. Does effectiveness and comparative effectiveness of urate lowering therapy differ according to disease severity (including presence of tophi and baseline serum UA), underlying mechanisms of hyperuricemia, or baseline demographic and co-morbid characteristics?
  3. What is the effect of dietary modification in combination with pharmacologic therapy?
Key Question 4: Treatment Monitoring of Patients with Gout
  1. In adults with gout, does monitoring serum urate levels with pharmacologic treatment and/or dietary and/or lifestyle change measures (e.g., compliance) improve treatment outcomes?
  2. Is achieving lower subsequent serum urate levels (less than 5 vs. 5–7mg/dL) associated with decreased risk for recurrent acute gout attack, progression to chronic arthritis or disability, resolution of tophi, or other clinical outcomes (including risk for comorbidities or progression of comorbidities) or patient-reported outcomes?
Key Question 5: Discontinuation of Pharmaceutical Management for Patients on Acute or Chronic Gout Medications

In adults with gout, are there criteria that can identify patients who are good candidates for discontinuing—

  1. urate lowering therapy?
  2. anti-inflammatory prophylaxis against acute gout attack for patients on urate lowering therapy after an acute gout attack?

Analytic Frameworks

We provide two analytic frameworks: one for acute gout (Figure A) and one for chronic gout (Figure B).

Figure A. Analytic framework for treatment of acute gout

This figure depicts Key Questions 1, 2, and 5 within the context of the PICOTS described in the previous section to create an analytic framework for the treatment of acute gout. The figure begins with the condition of acute gout. Key question 1 addresses the effects and potential harms (adverse events) associated with pharmacological treatment for an acute gout episode (flare), including the use of NSAIDS, corticosteroids (either oral or infused), and/or colchicine. Key question 2 addresses the role of dietary and/or lifestyle modifications, including a low purine diet, alcohol restriction, improved hydration, use of dietary supplements, increased physical activity, and other changes. In the center of the figure, a box lists possible short-term health outcomes, including pain, joint swelling, and tenderness (short-term being defined as 1-2 days to about a week). An additional potential short term harm is the risk for adverse events. Longer-term outcomes, depicted to the far right, include serum uric acid concentrations, pain, joint swelling and tenderness, ADLs, patient global assessment, and recurrence.

ADLs = activities of daily living; KQ = Key Question; sUA = serum uric acid; ULT = urate lowering therapy

Figure B. Analytic framework for management of chronic gout

This figure depicts key questions 2 through 5 within the context of the PICOTS described in the previous section to create an analytic framework for the treatment of chronic gout. Key question 2 addresses the role of dietary and/or lifestyle modifications, including a low purine diet, alcohol restriction, improved hydration, use of dietary supplements, increased physical activity, and other changes. Key question 3 addresses the possible outcomes of treating patients with chronic gout with urate lowering therapies (with or without prophylactic use of colchicine or NSAIDS to avert a gout flare). Potential effect modifiers to be considered include extent of disease (e.g., as assessed by presence of tophi), serum uric acid levels achieved, comorbidities, compliance, and other patient characteristics, as identified. Key question 4 specifically addresses the impact of monitoring of serum uric acid levels on progression and control. Intermediate health outcomes include serum uric acid levels. Longer-term (final) health outcomes may include pain, joint swelling, tenderness associated with development of tophi, ADLs, patient global assessment, risk for comorbidities/mortality, and recurrence of gout flares, as well as adverse effects of the treatments. Key question 5 addresses the impact of discontinuation to identify factors that might allow discontinuation of pharmacotherapy.

ADLs = activities of daily living; KQ = Key Question; sUA = serum uric acid; ULT = urate lowering therapy

Methods

In general, this systematic review follows the procedures of the January 2014 edition of the "Methods Guide for Effectiveness and Comparative Effectiveness Reviews."11

Searching for the Evidence

We searched multiple databases for systematic reviews on gout and studies not included in those systematic reviews. In general, we include studies of effectiveness only if they were randomized controlled trials. If no trials could be identified of interest, observational studies were included for assessing the role of nutrition. Observational studies were also included for rare adverse events. Evidence obtained through the systematic review process was considered in light of what is already known about the physiology of gout and about the treatment of painful and inflammatory conditions.

Literature Search Strategies for Identification of Relevant Studies to Answer the Key Questions

We searched PubMed, EMBASE, the Cochrane Collection, and the Web of Science using the search terms "gout" and "gouty," and terms for tophi (January 1, 2010-April 23, 2015; at least one year prior to the search dates for the recent systematic reviews). We also obtained relevant references from at least 28 recent systematic reviews that cover nearly all of the KQs. We also searched Clinicaltrials.gov and the Web of Science for recently completed studies and unpublished or non-peer-reviewed study findings. Searches were not limited by language of publication. We contacted manufacturers of the prescription medications used to treat gout that are listed in Table A for unpublished data specific to the use of these medications for treatment of gout or symptoms related to gout. We also included any relevant studies identified in the searches we conducted for a simultaneous review on diagnosis of gout if not already identified in the searches for this review. Finally, we asked the TEP to assess our list of included studies and to provide references for any additional studies they believed should also be included.

Data Abstraction and Data Management

Study level details from articles accepted for inclusion were abstracted by one reviewer and double checked by a second reviewer. Any disagreements were reconciled by the SCEPC Director, or the local subject matter expert if needed.

Assessment of Methodological Risk of Bias of Individual Studies

Risk of bias (study quality) of individual included studies was assessed independently by two reviewers using an adapted Cochrane Risk of Bias tool,12 and assessments were reconciled, with any disagreements mediated by the project lead. We used a modified AMSTAR tool to assess the quality of existing systematic reviews that we included;13 AMSTAR assessments were also conducted independently by two reviewers and reconciled.

Data Synthesis/Analysis

Given the large number of existing systematic reviews on this topic, we used the following strategy for data synthesis/analysis:

  1. Identify the existing systematic reviews and make a judgment about relevancy for the KQs, the end date of the search, and the methodologic quality as assessed by AMSTAR,13 following the process outlined by Whitlock and colleagues.14
  2. Scan the references of these systematic reviews for included studies.
  3. Search for new studies meeting the eligibility criteria for the KQ.
  4. Compare the conclusions of the existing systematic reviews.
  5. Compare the results of new studies with the conclusions of existing systematic reviews.
  6. Use the guide shown in Figure C for additional analyses/conclusions.

Figure C. Framework for incorporating existing systematic reviews and studies not included in these reviews

Figure C. Framework for incorporating existing systematic reviews and studies not included in these reviews - Description: This figure is a flow diagram on the strategy that was used for data synthesis/analysis. The steps are described more in detail right above the figure.

SR(s) = systematic review(s)

Grading the Strength of Evidence (SoE) for Major Comparisons and Outcomes

We assessed the overall SoE for each conclusion (e.g., the efficacy and safety of each pharmacologic agent or class of agents listed in the PICOTs (Participants, Interventions, Control, Outcome, and Timeframe and Setting), and differences by subgroup, if identified), using guidance suggested by the Effective Health Care Program.11 This method is based on one developed by the GRADE Working Group and classifies the grade of evidence as High (also called Strong), Moderate, Low or Insufficient. The evidence grade is based on five required domains: study limitations, consistency, directness, precision, and publication bias. The grades and their definitions are presented below.11

High: We are very confident that the estimate of effect lies close to the true effect for this outcome. The body of evidence has few or no deficiencies. We believe that the findings are stable, i.e., another study would not change the conclusions.

Moderate: We are moderately confident that the estimate of effect lies close to the true effect for this outcome. The body of evidence has some deficiencies. We believe that the findings are likely to be stable, but some doubt remains.

Low: We have limited confidence that the estimate of effect lies close to the true effect for this outcome. The body of evidence has major or numerous deficiencies (or both). We believe that additional evidence is needed before concluding either that the findings are stable or that the estimate of effect is close to the true effect.

Insufficient: We have no evidence, we are unable to estimate an effect, or we have no confidence in the estimate of effect for this outcome. No evidence is available or the body of evidence has unacceptable deficiencies, precluding reaching a conclusion.

We also considered in our strength of evidence assessments the criteria proposed by Bradford Hill for causality.15 These criteria include the strength, consistency, and specificity of the association, the temporal relationship, the "biologic gradient" or dose-response curve, the biologic plausibility, and coherence. These principles allow us to construct and evaluate evidence chains. For example, in assessing the evidence regarding pharmacological urate lowering therapy (ULT) agents, we considered the biochemical properties of urate in serum: urate is soluble in serum up to a concentration of about 6.0-7.0mg/dl. Numerous cohort studies show a gradient of gout attacks related to increasing serum urate levels. RCTs of ULT have demonstrated evidence that they lower serum urate levels, but the longest trials have lasted only 6 to 12 months and have not shown reductions in acute gout attacks in part because the same pharmaceutical interventions increase the risk of acute gout attacks in the short term (months). Long term observational extension studies from these RCTs show that patients who continued on pharmaceutical therapy had reduced serum urate levels and after about 1 year, a <5 percent risk of acute gout attacks. This evidence chain includes biologic plausibility, consistency of association, the appropriate temporal relationship, experimental evidence, the biologic gradient, and coherence. We rated this chain of evidence as moderate for pharmaceutical therapies to reduce the risk of acute gout attacks after about 1 year.

Assessing Applicability

Because the charge for this review is clear on the setting, care providers, and patient population the review is intended to cover, applicability assessment was based primarily on the similarity of the settings and populations to those for which this report is intended, namely primary and acute care settings that treat individuals, a high proportion of whom have comorbidities or are at risk for comorbidities such as hypertension and renal insufficiency.16

Peer Review and Public Commentary

A draft version of the report was posted for peer review on June 25 2015, and revised in response to reviewer comments.

Results

This section first describes the results of the literature searches, followed by descriptions of the studies that met inclusion criteria for each of the KQs and the key points (conclusions).

Results of Literature Searches

Our searches identified 6,269 titles/abstracts. Reference mining the previous systematic reviews (SRs) and guidelines identified in our searches resulted in an additional 233 titles. Our search of clinicaltrials.gov identified 270 entries for gout. Of these 19 were potentially relevant, 10 were either included already in our report or identified in our searches and excluded as ineligible, 1 was withdrawn, and 8 were recorded as being completed but no results were posted in clinicaltrials.gov, and we could find no published journal articles. Two manufacturers of drugs (Novartis and Regeneron) responded to requests by the AHRQ Scientific Resource Center for Scientific Information Packets on gout treatments. None of the trials described in these information packets was included in this report, as the drugs are currently not-FDA approved. Of a total of 6,772 titles/abstracts screened for inclusion. 6,087 titles/abstracts were excluded. At full text screening review, we rejected an additional 542 articles. Therefore, a total of 143 articles were included in our review.

For KQ 1, we included a total of 45 studies of which 15 were included in our analysis (3 RCTs, 2 studies that reported only on adverse events [AEs], and 10 systematic reviews [SRs]). The remaining 30 studies were identified in prior SRs. For KQ2, we included 22 studies of which 17 were included in our analysis (6 RCTs that examined dietary, lifestyle, Traditional Chinese Medicine [TCM] treatment, 3 observational studies [reported in 6 publications] on dietary factors, and 5 SRs). The remaining 10 studies were identified in prior SRs. For KQ3, we include a total of 55 studies of which 45 were included in our analysis (7 RCTs, 1abstract that has not been published, 5 secondary analyses, 20 studies that reported on AEs, 11 SRs and 1meta-analysis). The remaining 10 studies were identified in prior SRs. For KQ4, we include a total of 26 studies (24 original studies and 2 SRs). For KQ5, we include three original studies. See Figure D for the literature flow diagram.

Figure D. Literature flow diagram

This illustrates what is described in the section, Results of Literature Searches.

AE(s) = adverse event(s); KQ = Key Question; MA = meta-analysis; RCT(s) = randomized controlled trial(s); SR(s) = systematic review(s)

Findings

The key findings and SoE are in Table B.

Key Questions 1a–c. Acute Gout Treatment

  1. In patients with acute gout, what are the benefits and harms of different pharmacological therapies?
  2. Does effectiveness (benefits and harms) differ according to patient baseline demographic characteristics and co-morbid conditions (including renal function)?
  3. Does effectiveness (benefits and harms) differ according to disease severity, including initial clinical presentation (e.g., extent of joint involvement and time since start of flare) and laboratory values (serum and/or urine UA levels)?
Description of Included Studies

We identified 10 SRs on the following acute gout therapies: colchicine, NSAIDs, corticosteroids, and animal-derived ACTH formulation.17-26 We further identified three new trials not included in previous SRs that met our inclusion criteria,27-30 and two studies on adverse events (AEs).31,32

Key Findings and SoE for Key Questions 1a–c
  • High-strength evidence supports the efficacy of colchicine to reduce pain in acute gout.
  • Moderate-strength evidence supports the finding that low-dose colchicine is as effective as higher dose for reducing pain, with fewer side effects.
  • High-strength evidence supports the efficacy of NSAIDs to reduce pain in acute gout.
  • Moderate-strength evidence supports a lack of difference among NSAIDs in effectiveness.
  • High-strength evidence supports the efficacy of systemic corticosteroids to reduce pain in acute gout.
  • Moderate-strength evidence supports animal-derived ACTH formulation to reduce pain in acute gout.
  • SoE is insufficient regarding the effect of therapies on other outcomes: joint swelling, tenderness, activities of daily living, patient global assessment.
  • SoE is insufficient regarding differences in efficacy stratified by patient demographic, comorbid conditions, disease severity, clinical presentation, or lab values.
  • The most common adverse effects associated with colchicine are gastrointestinal symptoms, reported in 23 to 77 percent of users. NSAIDs also have gastrointestinal side effects, with dyspepsia or abdominal pain occurring in 10 percent or more of patients and more serious GI perforations, ulcers, and bleeds occurring in fewer than one percent of users, although the risk is greater in patients older than 65 years of age. Both colchicine and NSAIDs require dose reduction in renal impairment. The adverse effects of corticosteroids and animal-derived ACTH formulation are mostly related to long term use, although dysphoria, elevation in blood glucose, immune suppression, and fluid retention may all occur, even with short term use, and cumulative doses from repeated short term courses may also cause harms similar to long term use.

Key Questions 2a–b. Dietary and Lifestyle Management of Gout

  1. In adults with gout, what are the benefits and harms of different dietary therapies and life style measures on intermediate (serum and/or urine UA levels) and final health outcomes (including recurrence of gout episodes and progression [e.g., development of tophi])?
  2. Does effectiveness and comparative effectiveness of dietary modification differ according to disease severity (including presence of tophi and baseline serum UA), underlying mechanisms of hyperuricemia, or baseline demographic and co-morbid characteristics?
Description of Included Studies

We identified five SRs that examined the efficacy of dietary and other lifestyle factors in the treatment of gout.21,33-36 In addition, we identified six original RCTs and three prospective observational studies (the latter described in six publications) not included in previous SRs that met our inclusion criteria and examined dietary and lifestyle interventions in gout management.37-48

Key Findings and SoE for Key Questions 2a–b
  • The SoE from RCTs that assess symptomatic outcomes is insufficient to support a role for specific dietary changes (including reducing intakes of dietary purines, protein, or alcohol; increasing intakes of cherries, modified milk products, or supplemental vitamin C; or achieving weight loss) in gout management.
  • The SoE is insufficient to support a role for gout-specific dietary advice (counseling about reducing red meat intake; avoiding offal, shellfish, and yeast-rich foods and beverages; and including low fat dairy products, vegetables, and cherries) compared with nonspecific dietary advice (counseling about the importance of weight loss and reduced alcohol intake) for reducing serum urate levels in patients with gout.
  • The SoE is insufficient to support or refute the effectiveness of Traditional Chinese Medicine (TCM; including herbs and acupuncture) on symptomatic outcomes.

Key Questions 3a–c. Pharmacologic Management of Hyperuricemia in Gout Patients

  1. In adults with gout, what are the benefits and harms of different pharmacological therapies on intermediate (serum and/or urine UA levels) and long-term clinical health outcomes (including recurrence of gout episodes and progression)?
  2. Does effectiveness and comparative effectiveness of urate lowering therapy differ according to disease severity (including presence of tophi and baseline serum UA), underlying mechanisms of hyperuricemia, or baseline demographic and co-morbid characteristics?
  3. What is the effect of dietary modification in combination with pharmacologic therapy?
Description of Included Studies

Our literature search identified 11 SRs10,49-58 and one meta-analysis.59 In addition, we identified one new abstract60 and five secondary analyses61-65 of trials already included in the SRs and seven new trials.30,47,66-70 For AEs, we included 20 studies.71-90

Key Findings and SoE for Key Questions 3a–c
  • High-strength evidence supports the finding that urate lowering therapy does not reduce the risk of acute gout attacks in the first 6 months.
  • Moderate-strength evidence supports a reduction in the risk of acute gout attacks after about 1 year of urate lowering therapy.
  • High-strength evidence supports the efficacy of urate lowering therapy in reducing serum urate.
  • High-strength evidence supports the finding of no difference between 40mg febuxostat and 300mg allopurinol in serum urate lowering.
  • Evidence is insufficient about the potential effect of the presence of tophi on the effectiveness and comparative effectiveness of allopurinol and febuxostat.
  • High-strength evidence suggests that prophylactic therapy with low dose colchicine or low dose NSAIDs when beginning urate lowering therapy reduces the risk of acute gout attacks.
  • Moderate-strength evidence supports the finding that longer courses of prophylaxis with colchicine or NSAIDs (>8 weeks) are more effective than courses of shorter duration to prevent acute gout attacks when initiating urate lowering therapy.
  • The SoE is insufficient that gout-specific dietary advice adds to the effectiveness of urate lowering therapy in reducing serum urate.
  • The most common adverse event associated with allopurinol is a skin rash, occurring in up to 5 percent of patients. While most of these are mild and reversible, serious skin reactions including Topic Epidermal Necrolysis and Stevens Johnson Syndrome have been reported. Allopurinol has been proposed as a cause of the DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms. These serious side effects are sufficiently rare that clinical trials lack power to detect them. The risk of DRESS is greatly increased in patients with the HLA-B*5801 allele. Some evidence indicates that allopurinol reactions are more likely to occur in the first six months of treatment.
  • Clinical expertise with febuxostat is less than with allopurinol. The most commonly reported adverse events in trials of febuxostat were abdominal pain, diarrhea, and musculoskeletal pain (5 percent-20 percent for each), but these rates were not statistically significantly different from those in placebo-treated patients. Rare skin reactions also occur with febuxostat.
  • High-strength evidence supports a lack of difference in overall adverse events between allopurinol 300mg and febuxostat 40mg. A systematic review that identified four RCTs comparing the safety of urate lowering therapies found no statistically significant differences in overall adverse events between allopurinol and febuxostat.

Key Questions 4a–b. Treatment Monitoring of Patients With Gout

  1. In adults with gout, does monitoring serum urate levels with pharmacologic treatment and/or dietary and/or lifestyle change measures (e.g., compliance) improve treatment outcomes?
  2. Is achieving lower subsequent serum urate levels (less than 5 vs. 5–7mg/dL) associated with decreased risk for recurrent acute gout attack, progression to chronic arthritis or disability, resolution of tophi, or other clinical outcomes (including risk for comorbidities or progression of comorbidities) or patient-reported outcomes?
Description of Included Studies

For KQ 4a, we identified one SR91 from which 16 original studies were referenced mined.92-107

For KQ 4b, we identified one SR108 and eight studies that addressed the question.109-116

Key Findings and SoE for Key Question 4
  • Evidence is insufficient to support or refute that monitoring serum urate improves outcomes.
  • Low-strength evidence supports the finding that treating to a specific target serum urate level reduces the risk of gout attacks. However, the only way to know if urate lowering therapy affects serum urate is by monitoring serum urate levels. Therefore, this logic supports some monitoring, although how often and to what target have not been experimentally tested.

Key Question 5. Discontinuation of Pharmaceutical Management for Patients on Acute or Chronic Gout Medications

In adults with gout, are there criteria that can identify patients who are good candidates for discontinuing-

  • urate lowering therapy?
  • anti-inflammatory prophylaxis against acute gout attack for patients on urate lowering therapy after an acute gout attack?
Description of Included Studies

We identified three observational (prospective cohort) studies117-119 and also used data from three RCTs that addressed duration of anti-inflammatory prophylaxis in urate lowering therapy trials.120-122

Key Findings and SoE for Key Question 5
  • The evidence is insufficient that discontinuing urate lowering therapy results in no increase in risk of acute gout attacks in gout patients who have completed 5 years of urate lowering therapy that kept serum urate levels <7mg/dl, and in whom subsequent annual serum urate levels (off of urate lowering therapy) stayed <7mg/dl.
  • Moderate-strength evidence supports the finding that prophylaxis for acute gout with low dose colchicine or NSAIDs when initiating urate lowering therapy results in fewer gout attacks when treatment is given for longer than 8 weeks.

Discussion

Key Findings and SoE

We found a large number of research studies about gout, yet only a relatively modest number of these studies provided evidence for some of our KQs, particularly for the treatment of acute gout: only a single placebo-controlled trial of NSAIDs for acute gout pain, two placebo controlled RCTs of colchicine, and none at all for corticosteroids or ACTH. Nevertheless, we were able to reach strong conclusions about the usefulness of these drugs because of some specific features of gout: Symptoms result from an inflammatory reaction to the deposition of urate crystals, which occurs when serum urate rises above its saturation point in the blood. Hence, in an era that predated the widespread practice of placebo-controlled trial testing of therapies, medications aimed at blocking the inflammatory response were tried as treatments. Steroids are one of the most powerful and effective anti-inflammatory medications available. Although no placebo-controlled RCTs have tested their use in acute gout, steroids have proven efficacy in other inflammatory conditions, which gives us confidence that they are effective in treating the inflammatory reaction in acute gout. At this point, a placebo-controlled trial of steroids in acute gout may well be unethical, as it would mean withholding therapies of known effectiveness (e.g., colchicine) from the placebo-treated group. Indeed, a recent, high profile study of the use of steroids in acute gout compared their use not to placebo, but to NSAIDs. Because NSAIDs also have no conclusive placebo-controlled trial evidence of their effectiveness in acute gout, could it be that this RCT, which found only minor differences in outcomes between the two treatments, actually was comparing two treatments that were equally ineffective? We think not. We believe that both drugs are effective in treating acute gout, and therefore judged the SoE as high that their use relieves symptoms by a clinically important amount—despite the lack of placebo-controlled RCT evidence.

With regard to chronic gout, we similarly used evidence from a number of sources to reach conclusions about the effectiveness of ULT at reducing the risk of acute gout attacks over time, despite the fact that this outcome has not been studied in any placebo-controlled trial of longer than a few months. We based our moderate SoE rating on the high strength evidence that ULT reduces serum urate, that serum urate level is a strong predictor of the risk of acute gout attacks, and that the open-label extension studies of randomized controlled trials of ULT have shown a graded relationship between the serum urate level achieved and the risk of acute gout attacks. We thus concluded that over time, possibly by 1 year from initiation of therapy, ULT reduces the risk of acute gout attacks. We also concluded, based on a comparison of the timing of the occurrence of acute gout attacks in the weeks following initiation of ULT, that longer courses of prophylactic treatment with colchicine or NSAIDs (greater than 8 weeks) are more effective than courses of treatment with durations of 8 weeks or less, since in the one RCT of urate lowering therapy where prophylactic colchicine or NSAIDs were continued for 6 months, no "spike" in acute gout attacks coincided temporally with the discontinuation of the prophylactic therapy, like that seen in other RCTs where prophylaxis was stopped at 8 weeks.

A third key finding of our review is that there is scant direct evidence about how much ULT to give (e.g. the concept of treating-to-a-target) and for how long to give it (are there any criteria about when ULT can be stopped, or if once started is treatment needed for life?).

The key findings and SoE are in Table B.

Findings in Relationship to What is Already Known

In general, our findings support the results of existing SRs. We did find a number of RCTs not included in prior reviews. Some of these studies were "first-of-their-kind," such as those testing a specific dietary therapy and the duration of colchicine prophylaxis. However, most new studies either confirmed prior knowledge, or, in the case of studies of novel treatments, were not sufficiently high quality for us to draw conclusions.

Applicability

Of the 115 studies assessed in detail (not counting SRs), only 9 studies explicitly stated that patients came only from, or the study included patients from, primary care sites (including the ED and urgent care settings). Furthermore, it is likely that patients enrolled in clinical trials differ from those commonly seen in primary care settings. In the major trials of ULT, the proportion of patients with tophi is greater than 20 percent120-123 whereas in a trial that explicitly enrolled patients from primary care, the proportion of patients with tophi was 10 percent. A population-based study of more than 50,000 gout patients in English primary care practices reported the proportion with tophi as 0.5 percent124 Patients enrolled in clinical trials usually have fewer comorbidities than those seen in practice, because clinical trials have exclusion criteria. Thus, in most trials, enrolled patients probably had more advanced gout, but were better on average with respect to their other health conditions, than patients typically seen in primary care settings. We thus judged this evidence of moderate applicability to primary care.

Implications for Clinical and Policy Decisionmaking

The implications of this review for clinical decision-making follow from the identification of which interventions for gout management have evidence of an effect on clinical outcomes, either directly or through a strong indirect evidence chain. Thus, the results in Table B will be useful in policy decision-making and in the development of practice guidelines.

Limitations of the Comparative Effectiveness Review Process

For many of the KQs of interest, data were not reported on the subgroups or outcomes of interest as specified in the KQs and analytic frameworks, limiting the comparative effectiveness review. For the portion of the review on Traditional Chinese Medicine (TCM), the variability in tested interventions made comparisons across studies not justified.

Limitations of the Evidence Base

The lack of studies specifically stating that they enrolled patients in primary care settings is a limitation, as is the lack of randomized controlled studies assessing clinical outcomes for ULT (such as recurrent acute gout flare after 1 year) and intervention studies of dietary therapies for management of chronic gout. Longer term studies will be needed to assess the degree to which ULT reduces acute gout attacks relative to the adverse events of long term use of the available medications.

Research Gaps

The concept of "treat-to-target" (TTT) in gout, while supported by indirect evidence, has been untested. Guidelines and recommendations about TTT thresholds already vary, for example, <6mg/dL for all gout patients versus <5mg/dL for patients with significant gout morbidity. However, for many gout patients in primary care practice whose gout is well controlled on ULT, no data support such targets. In fact, the results of one cohort study suggest that once gout has been asymptomatic for 5 years, ULT might be discontinued for many years (as long as serum urate levels remain acceptable, e.g., <7mg/dL).117 Therefore, the most important research gap is a RCT comparing different TTT levels in patients with gout and elevated serum urate.

Treatment decisions are likely to be preference-sensitive, and studies are needed to assess patient preferences for different outcomes (for example, to what degree do patient preferences differ for outcomes such as a decrease in risk from 2 percent to 0.5 percent for an acute gout attack in the coming year versus a 5 percent chance of a skin rash and a less than 1 percent chance of a very serious skin rash).

Likewise, in spite of the many observational studies linking dietary factors with risk for gout, few studies have assessed the effect of specific dietary advice. Some dietary advice, such as generic advice to lose weight in overweight and obese patients, has evidence of benefit for other conditions and can be advocated in gout patients without additional data (e.g., it is always indicated to recommend dietary weight loss in patients who are obese). But primary care providers could more confidently recommend gout-specific dietary advice if compelling evidence supported an effect of such dietary changes on the risk for gout attacks or other gout-related outcomes. Therefore, another important research gap is evidence from RCTs for specific dietary changes (such as reducing or eliminating sugar-sweetened beverages or high-fructose foods, adequate hydration, restriction of alcohol, increase in low fat dairy consumption, and even restriction of high purine foods) compared with standard healthy diet advice and weight loss in reducing the risk of gout attacks.

A third research gap is the better characterization of adverse events from ULT and how they may be minimized. If the rare but serious adverse events from ULT could be further minimized, for example by HLA typing for predisposition, then the benefit/risk profile of ULT would further improve and make more patients eligible for treatment.

An additional research gap concerns prophylaxis when initiating ULT therapy. The optimal duration of such therapy has not been experimentally tested, and the comparative benefits/risks of all three agents used for acute attacks (colchicine, NSAIDs, oral steroids) have not been established.

Conclusions

Several drugs show moderate-to-high evidence of benefit in terms of reducing pain in patients with acute gout. It is clear that urate lowering therapy achieves its goal of lowering urate levels. Decreased serum urate should lead, over time, to a reduction in gout attacks, but the benefits and harms of long term urate lowering therapy have yet to be demonstrated directly. Patient preferences are likely to be important in decision-making (as specified above), and having better estimates of the size of the benefit of urate lowering therapy will make clinicians and patients more knowledgeable about the risk: benefit trade-off for the different decisions.

References

  1. Geronikolou SA. Treatment of gout in a recently published 9th century manuscript of Rhazes. Vesalius. 2014 Winter;20(2):95-8. PMID: 25739155.
  2. De Miguel E, Puig JG, Castillo C, et al. Diagnosis of gout in patients with asymptomatic hyperuricaemia: A pilot ultrasound study. Ann Rheum Dis. 2012 January;71(1):157-8. PMID: 2011671627 MEDLINE PMID 21953340
  3. Singh JA, Reddy SG, Kundukulam J. Risk factors for gout and prevention: a systematic review of the literature. Curr Opin Rheumatol. 2011 Mar;23(2):192-202. PMID: 21285714.
  4. Diagnosis of Gout Protocol. Rockville, MD: Agency for Health Care Research and Quality, Effective Health Care Program; July 17, 2014. www.effectivehealthcare.ahrq.gov/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=1992. Accessed on July 17 2014.
  5. Doghramji PP, Wortmann RL. Hyperuricemia and gout: new concepts in diagnosis and management. Postgrad Med. 2012 Nov;124(6):98-109. PMID: 23322143.
  6. Perez-Ruiz F, Hernandez-Baldizon S, Herrero-Beites AM, et al. Risk factors associated with renal lithiasis during uricosuric treatment of hyperuricemia in patients with gout. Arthritis Care Res (Hoboken). 2010 Sep;62(9):1299-305. PMID: 20506124
  7. Thompson GR, Duff IF, Robinson WD, et al. Long term uricosuric therapy in gout. Arthritis Rheum. 1962 Aug;5:384-96. PMID: 13920871.
  8. Anderson A, Singh Jasvinder A. Pegloticase for chronic gout. Cochrane Database Syst Rev: John Wiley & Sons, Ltd; 2010.
  9. Crittenden DB, Pillinger MH. New therapies for gout. Annu Rev Med. 2013;64:325-37. PMID: 23327525.
  10. Tayar Jean H, Lopez-Olivo Maria A, Suarez-Almazor Maria E. Febuxostat for treating chronic gout. Cochrane Database Syst Rev: John Wiley & Sons, Ltd; 2012.
  11. Agency for Healthcare Research and Quality. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. AHRQ Publication No. 10(14)-EHC063-EF. Rockville, MD: Agency for Healthcare Research and Quality. January 2014. Chapters available at: www.effectivehealthcare.ahrq.gov.
  12. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. PMID: 22008217.
  13. Shea BJ, Grimshaw JM, Wells GA, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol. 2007;7:10. PMID: 17302989.
  14. Whitlock EP, Lin JS, Chou R, et al. Using existing systematic reviews in complex systematic reviews. Ann Intern Med. 2008 May 20;148(10):776-82. PMID: 18490690.
  15. Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965 May;58:295-300. PMID: 14283879.
  16. Atkins D, Chang S, Gartlehner G, et al. Assessing the Applicability of Studies When Comparing Medical Interventions. Agency for Healthcare Research and Quality; December 2010. Methods Guide for Comparative Effectiveness Reviews. AHRQ Publication No. 11-EHC019-EF.
  17. Wechalekar Mihir D, Vinik O, Schlesinger N, et al. Intra-articular glucocorticoids for acute gout. Cochrane Database Syst Rev: John Wiley & Sons, Ltd; 2013.
  18. Moi John HY, Sriranganathan Melonie K, Edwards Christopher J, et al. Lifestyle interventions for acute gout. Cochrane Database Syst Rev: John Wiley & Sons, Ltd; 2013.
  19. Janssens Hein J, Lucassen Peter LBJ, Van de Laar Floris A, et al. Systemic corticosteroids for acute gout. Cochrane Database Syst Rev: John Wiley & Sons, Ltd; 2008.
  20. Daoussis D, Antonopoulos I, Andonopoulos AP. ACTH as a treatment for acute crystal-induced arthritis: Update on clinical evidence and mechanisms of action. Semin Arthritis Rheum. 2014 Apr;43(5):648-53. PMID: 24762710.
  21. Khanna PP, Gladue HS, Singh MK, et al. Treatment of acute gout: A systematic review. Semin Arthritis Rheum. 2014 Feb 13. PMID: 24650777.
  22. Richette P, Bardin T. Colchicine for the treatment of gout. Expert Opin Pharmacother. 2010 Dec;11(17):2933-8. PMID: 21050036.
  23. Terkeltaub RA. Colchicine Update: 2008. Seminars in Arthritis Rheum. 2009 Jun;38(6):411-9. PMID: WOS:000267026600001.
  24. van Echteld I, Wechalekar Mihir D, Schlesinger N, et al. Colchicine for acute gout. Cochrane Database Syst Rev: John Wiley & Sons, Ltd; 2014.
  25. Wechalekar MD, Vinik O, Moi JHY, et al. The efficacy and safety of treatments for acute gout: Results from a series of systematic literature reviews including cochrane reviews on intraarticular glucocorticoids, colchicine, nonsteroidal antiinflammatory drugs, and interleukin-1 inhibitors. J Rheumatol. 2014;41(SUPPL. 92):15-25.
  26. van Durme CM, Wechalekar MD, Buchbinder R, et al. Non-steroidal anti-inflammatory drugs for acute gout. Cochrane Database Syst Rev. 2014;9:CD010120. PMID: 25225849.
  27. Li T, Chen SL, Dai Q, et al. Etoricoxib versus indometacin in the treatment of Chinese patients with acute gouty arthritis: a randomized double-blind trial. Chin Med J (Engl). 2013;126(10):1867-71. PMID: 23673101.
  28. Taylor TH, Mecchella JN, Larson RJ, et al. Initiation of allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial. Am J Med. 2012 Nov;125(11):1126-34 e7. PMID: 23098865.
  29. Zhang YK, Yang H, Zhang JY, et al. Comparison of intramuscular compound betamethasone and oral diclofenac sodium in the treatment of acute attacks of gout. Int J Clin Pract. 2014 May;68(5):633-8. PMID: 24472084.
  30. Karimzadeh H, Nazari J, Mottaghi P, et al. Different duration of colchicine for preventing recurrence of gouty arthritis. J Res Med Sci. 2006;11:104-7.
  31. Almalki Z, Guo JJ, Kelton CM, et al. Adverse events associated with colchicine drug interactions: Analysis of the public version of the FDA adverse event reporting system. Value in Health. 2013 May;16(3):A218.
  32. Singh J, Yang S, Foster J. The risk of aplastic anemia and pancytopenia with colchicine: A retrospective study of integrated health system database. Arthritis Rheumatol. 2014 October; 66 SUPPL. 10:S20.
  33. Zhou L, Liu L, Liu X, et al. Systematic review and meta-analysis of the clinical efficacy and adverse effects of Chinese herbal decoction for the treatment of gout. PLoS One. 2014;9(1):e85008. PMID: 24465466.
  34. Li XX, Han M, Wang YY, et al. Chinese herbal medicine for gout: a systematic review of randomized clinical trials. Clin Rheumatol. 2013 Jul;32(7):943-59. PMID: 23666318.
  35. Lee WB, Woo SH, Min BI, et al. Acupuncture for gouty arthritis: a concise report of a systematic and meta-analysis approach. Rheumatology (Oxford). 2013 Jul;52(7):1225-32. PMID: 23424263.
  36. Choi TY, Kim TH, Kang JW, et al. Moxibustion for rheumatic conditions: A systematic review and meta-analysis. Clinical Rheumatology. 2011 July;30(7):937-45. PMID: 2011350115 MEDLINE PMID 21331532.
  37. Dalbeth N, Chen P, White M, et al. Impact of bariatric surgery on serum urate targets in people with morbid obesity and diabetes: a prospective longitudinal study. Ann Rheum Dis. 2014 May 1;73(5):797-802. PMID: 24255548.
  38. Neogi T, Chen C, Niu J, et al. Alcohol quantity and type on risk of recurrent gout attacks: an internet-based case-crossover study. Am J Med. 2014 Apr;127(4):311-8. PMID: 24440541.
  39. Zhang Y, Chen C, Choi H, et al. Purine-rich foods intake and recurrent gout attacks. Ann Rheum Dis. 2012 Sep;71(9):1448-53. PMID: 22648933.
  40. Zhang Y, Neogi T, Chen C, et al. Cherry consumption and decreased risk of recurrent gout attacks. Arthritis Rheum. 2012 Dec;64(12):4004-11. PMID: 23023818.
  41. Zhu Y, Zhang Y, Choi HK. The serum urate-lowering impact of weight loss among men with a high cardiovascular risk profile: the Multiple Risk Factor Intervention Trial. Rheumatology (Oxford). 2010 Dec;49(12):2391-9. PMID: 20805117.
  42. Zhang Y, Woods R, Chaisson CE, et al. Alcohol consumption as a trigger of recurrent gout attacks. Am J Med. 2006 Sep;119(9):800 e13-8. PMID: 16945617.
  43. Dalbeth N, Ames R, Gamble GD, et al. Effects of skim milk powder enriched with glycomacropeptide and G600 milk fat extract on frequency of gout flares: a proof-of-concept randomised controlled trial. Ann Rheum Dis. 2012 Jun;71(6):929-34. PMID: 22275296.
  44. Zeng YC, Huang SF, Mu GP, et al. Effects of adjusted proportional macronutrient intake on serum uric acid, blood lipids, renal function, and outcome of patients with gout and overweight. Chinese Journal of Clinical Nutrition. 2012 August;20(4):210-4. PMID: 2012603533 FULL TEXT LINK http://dx.doi.org/10.3760/cma.j.issn.1674-635X.2012.04.004.
  45. Stamp LK, O'Donnell JL, Frampton C, et al. Clinically insignificant effect of supplemental vitamin C on serum urate in patients with gout: a pilot randomized controlled trial. Arthritis Rheum. 2013 Jun;65(6):1636-42. PMID: 23681955.
  46. Zhang SJ, Liu JP, He KQ. Treatment of acute gouty arthritis by blood-letting cupping plus herbal medicine. J Tradit Chin Med. 2010 Mar;30(1):18-20. PMID: 20397456.
  47. Holland R, McGill NW. Comprehensive dietary education in treated gout patients does not further improve serum urate. Intern Med J. 2015 Feb;45(2):189-94. PMID: 25495503.
  48. Wang Y, Wang L, Li E, et al. Chuanhu anti-gout mixture versus colchicine for acute gouty arthritis: a randomized, double-blind, double-dummy, non-inferiority trial. Int J Med Sci. 2014;11(9):880-5. PMID: 25013367.
  49. Manara M, Bortoluzzi A, Favero M, et al. Italian Society of Rheumatology recommendations for the management of gout. Reumatismo. 2013;65(1):4-21. PMID: 23550256.
  50. Faruque LI, Ehteshami-Afshar A, Wiebe N, et al. A systematic review and meta-analysis on the safety and efficacy of febuxostat versus allopurinol in chronic gout. Semin Arthritis Rheum. 2013 Dec;43(3):367-75. PMID: 24326033.
  51. Latourte A, Bardin T, Richette P. Prophylaxis for acute gout flares after initiation of urate-lowering therapy. Rheumatology (Oxford). 2014 Apr 23PMID: 24758886.
  52. Ramasamy SN, Korb-Wells CS, Kannangara DR, et al. Allopurinol hypersensitivity: a systematic review of all published cases, 1950-2012. Drug Saf. 2013 Oct;36(10):953-80. PMID: 23873481.
  53. Ye P, Yang S, Zhang W, et al. Efficacy and tolerability of febuxostat in hyperuricemic patients with or without gout: a systematic review and meta-analysis. Clin Ther. 2013 Feb;35(2):180-9. PMID: 23332451.
  54. Seth R, Kydd AS, Falzon L, et al. Preventing attacks of acute gout when introducing urate-lowering therapy: a systematic literature review. J Rheumatol Suppl. 2014 Sep;92:42-7. PMID: 25180127.
  55. Seth R, Kydd AS, Buchbinder R, et al. Allopurinol for chronic gout. Cochrane Database Syst Rev. 2014;10:CD006077. PMID: 25314636.
  56. Kydd AS, Seth R, Buchbinder R, et al. Uricosuric medications for chronic gout. Cochrane Database Syst Rev. 2014;11:CD010457. PMID: 25392987.
  57. Castrejon I, Toledano E, Rosario MP, et al. Safety of allopurinol compared with other urate-lowering drugs in patients with gout: a systematic review and meta-analysis. Rheumatol Int. 2014 Dec 18PMID: 25519877.
  58. van Echteld IA, van Durme C, Falzon L, et al. Treatment of gout patients with impairment of renal function: a systematic literature review. J Rheumatol Suppl. 2014 Sep;92:48-54. PMID: 25180128.
  59. Chohan S, Becker MA, MacDonald PA, et al. Women with gout: efficacy and safety of urate-lowering with febuxostat and allopurinol. Arthritis Care Res (Hoboken). 2012 Feb;64(2):256-61. PMID: 22052584.
  60. Saag KG, Becker MA, Whelton A, et al. Effect of febuxostat on serum urate levels in gout subjects with hyperuricemia and moderate-to-severe renal impairment: A randomized controlled trial. Arthritis Rheum. 2013 October;65 SUPPL. 10:S498-S9.
  61. Becker MA, MacDonald PA, Hunt B, et al. Treating hyperuricemia of gout: safety and efficacy of febuxostat and allopurinol in older versus younger subjects. Nucleosides Nucleotides Nucleic Acids. 2011 Dec;30(12):1011-7. PMID: 22132950.
  62. Becker MA, MacDonald PA, Hunt BJ, et al. Diabetes and gout: efficacy and safety of febuxostat and allopurinol. Diabetes Obes Metab. 2013 Nov;15(11):1049-55. PMID: 23683134.
  63. Goldfarb DS, MacDonald PA, Hunt B, et al. Febuxostat in gout: serum urate response in uric acid overproducers and underexcretors. J Rheumatol. 2011 Jul;38(7):1385-9. PMID: 21572152.
  64. Jackson RL, Hunt B, MacDonald PA. The efficacy and safety of febuxostat for urate lowering in gout patients ≥65 years of age. BMC Geriatr. 2012;12:11. PMID: 22436129.
  65. Wells AF, MacDonald PA, Chefo S, et al. African American patients with gout: efficacy and safety of febuxostat vs allopurinol. BMC Musculoskelet Disord. 2012;13:15. PMID: 22316106.
  66. Huang X, Du H, Gu J, et al. An allopurinol-controlled, multicenter, randomized, double-blind, parallel between-group, comparative study of febuxostat in Chinese patients with gout and hyperuricemia. Int J Rheum Dis. 2014 Jan 28. PMID: 24467549.
  67. Wortmann RL, Macdonald PA, Hunt B, et al. Effect of prophylaxis on gout flares after the initiation of urate-lowering therapy: analysis of data from three phase III trials. Clin Ther. 2010 Dec;32(14):2386-97. PMID: 21353107.
  68. Borstad GC, Bryant LR, Abel MP, et al. Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol. 2004 Dec;31(12):2429-32. PMID: 15570646.
  69. Gibson T, Rodgers V, Potter C, et al. Allopurinol treatment and its effect on renal function in gout: a controlled study. Ann Rheum Dis. 1982 Feb;41(1):59-65. PMID: 7039523.
  70. Scott JT. Comparison of allopurinol and probenecid. Ann Rheum Dis. 1966 Nov;25(6 Suppl):623-6. PMID: 5335059.
  71. Stamp LK, Taylor WJ, Jones PB, et al. Starting dose is a risk factor for allopurinol hypersensitivity syndrome: a proposed safe starting dose of allopurinol. Arthritis Rheum. 2012 Aug;64(8):2529-36. PMID: 22488501.
  72. Gilchrist MJ, Hebert B. Drug reaction with eosinophilia and systemic symptoms (DRESS). Journal of General Internal Medicine. 2011 May;26 SUPPL. 1:S423.
  73. Tassaneeyakul W, Jantararoungtong T, Chen P, et al. Strong association between HLA-B*5801 and allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a Thai population. Pharmacogenet Genomics. 2009 Sep;19(9):704-9. PMID: 19696695.
  74. Becker MA, Fitz-Patrick D, Storgard C, et al. A large-scale, multicenter, prospective, open-label, 6-month study to evaluate the safety of allopurinol monotherapy in patients with gout. Arthritis Rheum. 2013 October;65 SUPPL. 10:S502-S3.
  75. Chaudrey K, Khan M, Madhoun M, et al. Allopurinol-induced dress syndrome: A reversible fatality. American Journal of Gastroenterology. 2013 October;108 SUPPL. 1:S153.
  76. Ibie NC, Alper AB. She is all dressed up: A case of allopurinol deadly complication. Journal of Investigative Medicine. 2014 February;62(2):504-5.
  77. Weiss KM, Jain R, Wells C, et al. A case of allopurinol-induced dress syndrome in a patient with asymptomatic gout. Annals of Allergy, Asthma and Immunology. 2011 November;107(5 SUPPL. 1):A26.
  78. Kamatani N, Fujimori S, Hada T, et al. Multicenter, open-label study of long-term administration of febuxostat (TMX-67) in Japanese patients with hyperuricemia including gout. J Clin Rheumatol. 2011 Jun;17(4 Suppl 2):S50-6. PMID: 21654270.
  79. Yaylaci S, Demir MV, Temiz T, et al. Allopurinol-induced DRESS syndrome. Indian J Pharmacol. 2012 May;44(3):412-4. PMID: 22701258.
  80. Schumacher HR, Becker MA, Lloyd E, et al. Febuxostat in the treatment of gout: 5-yr findings of the FOCUS efficacy and safety study. Rheumatology. 2009 Feb;48(2):188-94. PMID: WOS:000262518500020.
  81. Lee MH, Stocker SL, Anderson J, et al. Initiating allopurinol therapy: do we need to know the patient's human leucocyte antigen status? Internal Medicine Journal. 2012 Apr;42(4):411-6. PMID: WOS:000302796000017.
  82. Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med. 1984 Jan;76(1):47-56. PMID: 6691361.
  83. Chen IH, Kuo MC, Hwang SJ, et al. Allopurinol-induced severe hypersensitivity with acute renal failure. Kaohsiung J Med Sci. 2005 May;21(5):228-32. PMID: 15960069.
  84. Kumar A, Edward N, White MI, et al. Allopurinol, erythema multiforme, and renal insufficiency. BMJ. 1996 Jan 20;312(7024):173-4. PMID: 8563541.
  85. Lupton GP, Odom RB. The allopurinol hypersensitivity syndrome. J Am Acad Dermatol. 1979 Oct;1(4):365-74. PMID: 159913.
  86. Chung WH, Chang WC, Stocker SL, et al. Insights into the poor prognosis of allopurinol-induced severe cutaneous adverse reactions: the impact of renal insufficiency, high plasma levels of oxypurinol and granulysin. Ann Rheum Dis. 2015 Dec;74(12):2157-64. PMID: 25115449.
  87. Singh JA, Yang S, Foster J. Increased risk of skin reactions with gout medications: An analysis of va databases. Arthritis Rheumatol. 2014 October;66 SUPPL. 10:S71.
  88. Ko TM, Wu JY, Chen YT, et al. A prospective study of HLAnullB-5801 genotyping in preventing allopurinol-induced severe cutaneous adverse reactions. Clinical and Translational Allergy. 2014 18;4 SUPPL. 3:2.
  89. Guy C, Lebrun-Vignes B, Jean-Pastor MJ. Drug-induced toxic epidermal necrolysis and Stevens-Johnson syndrome: Analysis of the French national pharmacovigilance database. Fundamental and Clinical Pharmacology. 2014 May;28 SUPPL. 1:65.
  90. Bardin T, Chales G, Pascart T, et al. Is the rate of skin reactions to febuxostat increased in patients with a history of skin intolerance to allopurinol? A retrospective, hospital-based study involving 101 patients consecutively treated with allopurinol and febuxostat. Arthritis Rheumatol. 2014 October;66 SUPPL. 10:S68.
  91. De Vera M, Rai S, Bhole V. Medication adherence in patients with gout: A systematic review. Arthritis and Rheumatism. 2013 October;65 SUPPL. 10:S85.
  92. Zandman-Goddard G, Amital H, Shamrayevsky N, et al. Rates of adherence and persistence with allopurinol therapy among gout patients in Israel. Rheumatology (Oxford). 2013 Jun;52(6):1126-31. PMID: 23392592.
  93. Martini N, Bryant L, Karu LT, et al. Living with gout in New Zealand: an exploratory study into people's knowledge about the disease and its treatment.J Clin Rheumatol. 2012 Apr;18(3):125-9. PMID: WOS:000302141900003.
  94. Silva L, Miguel ED, Peiteado D, et al. Compliance in gout patients. Acta Reumatol Port. 2010 Oct-Dec;35(5):466-74. PMID: 21245815.
  95. Harrold LR, Andrade SE, Briesacher B, et al. The dynamics of chronic gout treatment: medication gaps and return to therapy. Am J Med. 2010 Jan;123(1):54-9. PMID: 20102992.
  96. Harrold LR, Andrade SE, Briesacher BA, et al. Adherence with urate-lowering therapies for the treatment of gout. Arthritis Res Ther. 2009;11(2):R46. PMID: 19327147.
  97. Halpern R, Mody RR, Fuldeore MJ, et al. Impact of noncompliance with urate-lowering drug on serum urate and gout-related healthcare costs: administrative claims analysis. Curr Med Res Opin. 2009 Jul;25(7):1711-9. PMID: 19485724.
  98. Riedel AA, Nelson M, Joseph-Ridge N, et al. Compliance with allopurinol therapy among managed care enrollees with gout: a retrospective analysis of administrative claims. J Rheumatol. 2004 Aug;31(8):1575-81. PMID: 15290738.
  99. Rascati K, Prasla K, Park H, et al. Evaluation of healthcare costs for patients with gout by serum uric acid. Arthritis Rheum. 2011;63(10):2011-11.
  100. Dalbeth N, House ME, Horne A, et al. Prescription and dosing of urate-lowering therapyy, rather than patient behaviours, are the key modifiable factors associated with targeting serum urate in gout. BMC Musculoskelet Disord. 2012;13:174. PMID: 22978848.
  101. Dalbeth N, Petrie KJ, House M, et al. Illness perceptions in patients with gout and the relationship with progression of musculoskeletal disability. Arthritis Care Res (Hoboken). 2011 Nov;63(11):1605-12. PMID: 22034122.
  102. Singh JA, Hodges JS, Asch SM. Opportunities for improving medication use and monitoring in gout. Ann Rheum Dis. 2009 Aug;68(8):1265-70. PMID: WOS:000268010500006.
  103. Sarawate CA, Brewer KK, Yang W, et al. Gout medication treatment patterns and adherence to standards of care from a managed care perspective. Mayo Clin Proc. 2006 Jul;81(7):925-34. PMID: 16835972.
  104. Solomon DH, Avorn J, Levin R, et al. Uric acid lowering therapy: prescribing patterns in a large cohort of older adults. Ann Rheum Dis. 2008 May;67(5):609-13. PMID: 17728328.
  105. Briesacher BA, Andrade SE, Fouayzi H, et al. Comparison of drug adherence rates among patients with seven different medical conditions. Pharmacotherapy. 2008 Apr;28(4):437-43. PMID: 18363527.
  106. de Klerk E, van der Heijde D, Landewe R, et al. Patient compliance in rheumatoid arthritis, polymyalgia rheumatica, and gout. J Rheumatol. 2003 Jan;30(1):44-54. PMID: 12508389.
  107. Deyo RA, Inui TS, Sullivan B. Noncompliance with arthritis drugs: magnitude, correlates, and clinical implications. J Rheumatol. 1981 Nov-Dec;8(6):931-6. PMID: 7328568.
  108. Andres M, Sivera F, Falzon L, et al. Treatment target and followup measures for patients with gout: a systematic literature review. J Rheumatol Suppl. 2014 Sep;92:55-62. PMID: 25180129.
  109. Krishnan E, Akhras KS, Sharma H, et al. Serum urate and incidence of kidney disease among veterans with gout. J Rheumatol. 2013 Jul;40(7):1166-72. PMID: 23678154.
  110. Wu EQ, Patel PA, Mody RR, et al. Frequency, risk, and cost of gout-related episodes among the elderly: does serum uric acid level matter? J Rheumatol. 2009 May;36(5):1032-40. PMID: 19369467.
  111. Halpern R, Fuldeore MJ, Mody RR, et al. The effect of serum urate on gout flares and their associated costs: an administrative claims analysis. J Clin Rheumatol. 2009 Feb;15(1):3-7. PMID: 19125135.
  112. Becker MA, MacDonald PA, Hunt BJ, et al. Determinants of the clinical outcomes of gout during the first year of urate-lowering therapy. Nucleosides Nucleotides Nucleic Acids. 2008 Jun;27(6):585-91. PMID: 18600509.
  113. Sarawate CA, Patel PA, Schumacher HR, et al. Serum urate levels and gout flares: analysis from managed care data. J Clin Rheumatol. 2006 Apr;12(2):61-5. PMID: 16601538.
  114. Bongartz T, Zleik N, Clement M, et al. The risk of future attacks in patients with incident gout: A population-based. Ann Rheum Dis. 2013;72(3):2013-06.
  115. Hamburger MI, Tesser JRP, Skosey JL, et al. Patterns of gout treatment and related outcomes in us community rheumatology practices: The relation between gout flares, time in treatment, serum uric acid level and urate lowering therapy. Arthritis Rheum. 2012 October;64 SUPPL. 10:S808-S9.
  116. Khanna PP, Baumgartner S, Khanna D, et al. Assessing SUA, flare rates, and Tophi in patients with gout treated xanthine oxidase inhibitors in the United States. Ann Rheum Dis. 2013;72(3):2013-06.
  117. Perez-Ruiz F, Herrero-Beites AM, Carmona L. A two-stage approach to the treatment of hyperuricemia in gout: the "dirty dish" hypothesis. Arthritis Rheum. 2011 Dec;63(12):4002-6. PMID: 21898351.
  118. Loebl WY, Scott JT. Withdrawal of allopurinol in patients with gout. Ann Rheum Dis. 1974 Jul;33(4):304-7. PMID: 4416909.
  119. Perez-Ruiz F, Atxotegi J, Hernando I, et al. Using serum urate levels to determine the period free of gouty symptoms after withdrawal of long-term urate-lowering therapy: a prospective study. Arthritis Rheum. 2006 Oct 15;55(5):786-90. PMID: 17013833.
  120. Becker MA, Schumacher HR, Jr., Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005 Dec 8;353(23):2450-61. PMID: 16339094.
  121. Schumacher Jr HR, Becker MA, Wortmann RL, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: A 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Care Res. 2008;59(11):1540-8.
  122. Becker MA, Schumacher HR, Espinoza LR, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther. 2010;12(2):R63. PMID: 20370912.
  123. Becker MA, Schumacher HR, MacDonald PA, et al. Clinical efficacy and safety of successful longterm urate lowering with febuxostat or allopurinol in subjects with gout. J Rheumatol. 2009 Jun;36(6):1273-82. PMID: WOS:000266891500030.
  124. Kuo CF, Grainge MJ, Mallen C, et al. Eligibility for and prescription of urate-lowering treatment in patients with incident gout in England. JAMA. 2014 Dec 24-31;312(24):2684-6. PMID: 25536262.

Citation

This executive summary is part of the following document: Shekelle PG, FitzGerald J, Newberry SJ, Motala A, O'Hanlon CE, Okunogbe A, Tariq A, Han D, Dudley W, Shanman R, Booth M. Management of Gout. Comparative Effectiveness Review No. 176. (Prepared by the RAND Southern California Evidence-based Practice Center under Contract No. 290-2012-00006-I.) AHRQ Publication No.16-EHC017-EF. Rockville, MD: Agency for Healthcare Research and Quality; March 2016.

Tables

Table A. Pharmacologic agents used in the treatment of gout
Drug Class Agent (generic/brand) Manufacturer
aThese agents will not be considered in this review, because they are not FDA-approved for use in treating gout and/or are not prescribed in the primary care setting.
Anti-inflammatory Agents for Gout Attacks NSAIDS (including Ibuprofen, naproxen, etodolac, diclofenac, indomethacin, COX-2 inhibitors) Numerous
Corticosteroids/ Animal-derived adrenocorticotropic hormone (ACTH) formulation Numerous
Colchicine/ColcrysTM, Colchicine tablets, USP authorized generic Takeda Pharmaceuticals, America, Inc.
IL-1B Receptor Antagonists:a Anakinra/kineret® Sobi
Urate Lowering Agents Uricosurics: Probenecid/Benemid® or Probalan Multiple
Xanthine Oxidase Inhibitors: Allopurinol/Zyloprim® Prometheus Labs
Febuxostat/UloricTM Teijin Pharma Ltd., Takeda
Uricase: Pegloticase/Krystexxa®a Crealta
Combination agents: Colchicine-probenecid/Proben-C Merck
Table B. Summary of prior knowledge, findings from the systematic review, and strength of evidence, by KQ
Key Question Findings Prior Knowledge Used in Determining Strength of Evidence Sources of Evidence Included in This Systematic Review Strength of Evidence
FDA = Food and Drug Administration; N/A = not applicable; NSAID = nonsteroidal anti-inflammatory drug; RCT = randomized controlled trial; ULT = urate lowering therapy
KQ1 Acute Gout Treatment Colchicine reduces pain N/A 2 placebo-controlled RCTs (N=45 and N=184) both with low risk of bias High
Low-dose colchicine is as effective as higher dose for reducing pain, with fewer side effects N/A 1 head-to-head RCT with low risk of bias (N=184) Moderate
NSAIDs reduce gout pain
  • Biologic rationale (anti-inflammatory action)
  • Placebo-controlled RCT evidence that NSAIDs provide temporary pain relief for numerous conditions
  • 1 placebo-controlled RCT with high risk of bias (N=30)
  • High strength observational data (NSAID use as prophylaxis against gout flare) (see below under KQ3)  
High
No difference between NSAIDs in effectiveness Equivalence in effectiveness among NSAIDs in numerous other conditions 16 head-to-head RCTs Moderate
Systemic corticosteroids reduce pain Biologic rationale (anti-inflammatory action)
  • No placebo-controlled RCTs
  • Equivalence to NSAIDs in 4 RCTs (N=27, N=90, N=120, and N=60).Three of four RCTs had low risk of bias.
High
Animal-derived ACTH formulation reduces pain Biologic rationale (anti-inflammatory action)
  • No placebo-controlled RCTs
  • Equivalence to NSAIDs and intramuscular steroids in RCTs (one RCT of each, N=76 and N=31 both at high risk of bias)
Moderate
Differences stratified by patient demographic, comorbid conditions, disease severity, clinical presentation, or laboratory values N/A None of the included RCTs presented data stratified by these variables. Insufficient
KQ2 Diet and Lifestyle Management Specific dietary changes (including reducing intakes of dietary purines, protein, or alcohol; increasing intakes of cherries, modified milk products, or supplemental vitamin C; or achieving weight loss) in gout management may affect symptomatic outcomes N/A
  • 3 RCTs (two at high risk of bias) (N=67, N=120, N=40)
  • 3 observational studies (N=20, N=120, N=633)
Insufficient
Gout-specific dietary advice (counseling about reducing red meat; avoiding offal, shellfish, and yeast-rich foods and beverages or increasing low-fat dairy products, vegetables, and cherries) compared with nonspecific dietary advice (counseling about the importance of weight loss and reduced alcohol intake) for reducing serum urate levels in patients with gout N/A 1 RCT with high risk of bias (N=30) Insufficient
Effectiveness of Traditional Chinese Medicine (TCM) (acupuncture, herbal mixtures, moxibustion) on symptomatic outcomes N/A 86 RCTs, all of idiosyncratic therapies, with conflicting results Insufficient
KQ3 Management of Hyperuricemia Urate lowering therapy does not reduce the risk of acute gout attacks within the first 6 months N/A 2 placebo-controlled RCTs,with low risk of bias (N=1,072 and N=57) High
Urate lowering therapy reduces the risk of acute gout attacks after 1- year Acute gout attacks are caused by elevated serum urate concentrations
  • No placebo-controlled RCTs assess long-term risk of acute gout attacks
  • RCTs with low risk of bias show that ULT reduces serum uric acid
  • Open label extension study of ULT RCT shows reduced risk of acute gout attacks over time, plateauing at less than 5% at about 1 year
Moderate
Urate lowering therapy reduces serum urate N/A 4 placebo-controlled RCTs all with low risk of bias (N=1,072, N=96, N=153, and N=57) High
40 mg febuxostat and 300mg allopurinol show no differences in serum urate lowering N/A 1 head-to-head RCT with low risk of bias (N=2,269) High
Effectiveness and comparative effectiveness of allopurinol and febuxostat depending on the presence of tophi N/A Subgroup analyses of included trials did not report consistent results when stratified on the presence of tophi. Insufficient
Age and race (Caucasian vs. African-American) do not affect the efficacy of febuxostat or allopurinol. N/A Subgroup analyses of 1 head-to-head RCT with low risk of bias (N=2,269) Low
Prophylactic therapy with low-dose colchicine or low-dose NSAIDs when beginning urate lowering therapy reduces the risk of acute gout attacks N/A
  • 1 placebo-controlled RCT of colchicine 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, N=2,269, and N=1,072)
High
Longer durations of prophylaxis with colchicine or NSAIDs (> 8 weeks) are more effective than shorter duration when initiating urate lowering therapy N/A
  • Indirect evidence from comparisons across 3 RCTs of differing durations of prophylaxis
  • 1 RCT with high risk of bias (N=190)
Moderate
Specific gout-dietary advice to reduce red meat, shellfish, etc. while increasing low-fat dairy products, vegetables, and cherries does not add to the effectiveness of urate lowering therapy for reducing serum urate N/A 1 RCT with high risk of bias (N=30) Insufficient
KQ4 Treatment Monitoring Serum urate monitoring improves outcomes N/A
  • No direct evidence
  • An argument can be made indirectly, based on the evidence that elevated serum urate levels cause gout
Insufficient
Treating to a specific target serum urate level reduces the risk of gout attacks Lower serum urate levels are associated with reduced risk of gout attacks
  • No RCT evidence
  • Variable targets proposed or assessed in the literature
Low
KQ5 Criteria for Discontinuation of Pharmaceutical Management Hyperuricemia: Urate lowering therapy may be discontinued in gout patients with 5 years of urate lowering therapy keeping serum urate levels <7mg/dl, with subsequent annual off-urate lowering therapy-serum urate levels <7mg/dl N/A 3 prospective cohort studies (N=211, N=33, N=100) Insufficient
Prophylaxis: Prophylaxis for acute gout when initiating urate lowering therapy with low-dose colchicine or NSAIDs should be longer than 8 weeks N/A Indirect evidence from comparisons across 3 RCTs with low risk of bias of differing durations of prophylaxis (N=762, N=2,269, and N=1,072) Moderate