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Shekelle PG, FitzGerald J, Newberry SJ, et al. Management of Gout [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2016 Mar. (Comparative Effectiveness Reviews, No. 176.)
Background
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.
Based on data from the 2007-2008 National Health and Nutrition Examination Survey (NHANES), the prevalence of gout among adults in the United States was estimated to be 3.9 percent (8.3 million individuals), ranging from 2.0 percent in women to 5.9 percent in men.2 Comparing the most recent figures for the prevalence of gout to those of previous cycles of NHANES shows that the prevalence of gout appears to be increasing. The rise in the prevalence of gout has paralleled the increase in prevalence of conditions associated with hyperuricemia, including obesity, hypertension, hypertriglyceridemia, hypercholesterolemia, type 2 diabetes and metabolic syndrome, and chronic kidney disease.3 Certain dietary factors and medications also may increase the risk for developing gout (e.g., thiazide diuretics).
A 2013 study of ambulatory care costs associated with gout estimated the costs to be nearly $1 billion (in 2008 figures). Of this figure, 32 percent of the costs were attributed to office visits for acute attacks (flares), and 61 percent were attributed to expenditures for prescription medications to treat the condition.4
The aim of this report is to review the evidence for the efficacy and safety of treatments for 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. Over time, these attacks become prolonged and can become chronic. The acute gout attack is a result of urate (the salt form of uric acid [UA]) crystals directly interacting with the immune system. Several factors affect deposition of urate crystals, including temperature, local pH, and most critically, the concentration of serum urate. The solubility factor of urate is 6.8mg/dl; urate concentrations above this threshold lead to crystal deposition; levels below this threshold lead to crystal dissolution. UA is a breakdown product of dietary or endogenous purines, (which are among the building blocks of nucleic acids) and is associated with the formation and deposition of the UA crystals. Hyperuricemia can result from UA overproduction or inadequate renal excretion. The latter is far more common than the former, affecting 90 percent of patients: Renal disease and medications can affect the excretion of serum urate. As serum urate concentration rises above 6.0mg/dl, the risk for developing an acute gout attack increases. The Framingham Heart Study found that, among men, the 5-year incidence of acute gout attack increases from 10 percent when serum urate is between 6.0 and 6.9mg/dl to 48 percent for serum urate greater than 8mg/dl.5 Once a patient has had an initial attack, hyperuricemia increases the risk of repeat attacks. The 1-year incidence of recurrent attack is 30 percent for patients with serum urate between 6.0 and 6.9mg/dl and over 70 percent for patients with serum urate greater than 8mg/dl.6 Although the primary risk factor for gout is hyperuricemia, not all patients with hyperuricemia go on to develop clinical gout; hyperuricemia in the absence of 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).7 The prevalence of hyperuricemia is about 21 percent, four-to ten-fold higher than the prevalence of gout.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).8 Dietary risk factors are discussed further below. 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.9
Clinical Presentation and Management
Gout is commonly divided into 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.
A number of pharmacologic agents have been advocated for use in the management of acute gout. Commonly advocated agents to treat acute gout include non-steroidal anti-inflammatories (NSAIDS), colchicine (the microtubule disrupting agent), and/or corticosteroids (intra-articular or systemic) to manage pain and inflammation. The evidence for the efficacy of these agents in treating acute gout is a topic of this review.
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.10 The average interval between the onset of gout and appearance of tophi, in the absence of treatment, is approximately 10 years.10 Increased frequency of attacks and tophi are highly correlated with the presence of hyperuricemia. In addition to the aforementioned manifestations of chronic gout, patients with long standing gout can develop uric acid nephrolithiasis and chronic interstitial nephropathy. Gout has also been associated with a higher risk for progression of kidney disease11 and increased risk of atherosclerotic disease, including myocardial infarction, heart failure, and stroke.12
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 also fallen out of favor, because allopurinol was found to be effective in “underexcretors.”13, 14 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, based on observational evidence that particular dietary and other lifestyle factors are associated with a greater or lesser risk for developing gout. 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). Based on evidence that purines increase serum urate levels, avoidance of high–purine foods has been the mainstay of dietary management of gout for decades. Further evidence from recent trials and observational studies suggests that a number of additional dietary factors may affect the risk for gout or hyperuricemia.
A 2011 systematic review examined 53 observational studies that assessed the association of a variety of foods, other dietary factors, and other factors with the risk for incident gout.8 Meat intake, seafood intake, consumption of alcohol, consumption of sugar-sweetened beverages and other high-fructose foods, and overweight were associated with an increased risk for gout. A 2013 5-year prospective cohort study of hyperuricemic Chinese men that used a food frequency questionnaire found a significant association between consumption of shellfish, but not other foods, and risk for gout.15
A 2012 systematic review that included 18 RCTs examined the effects of fructose intake on serum urate levels in normo-glycemic and diabetic patients. The review included both studies in which fructose isocalorically replaced other dietary components and those that added fructose to increase the caloric load. The review found no increase in serum urate with isocaloric fructose consumption but high levels of fructose that increased overall calorie intake increased serum urate.16 Analysis of data from the large, observational Nurses' Health Study also found an association between consumption of fructose-sweetened beverages and increased risk for gout among women.17
The association between alcohol consumption and risk for incident gout was examined in a 2013 SR and meta-analysis that included 17 observational studies, reported in 12 articles.18 Light (≤1 drink/day), moderate (>1 to <3 drinks/day), and heavy (≥3 drinks/day) drinking were associated with significant increases in the risk for gout, compared with non- or occasional drinking (RR1.16 (95 % CI, 1.07–1.25), 1.58 (95 % CI, 1.50–1.66), and 2.64 (95 % CI, 2.26–3.09), respectively. We also identified an additional study not included in the 2013 SR that assessed the association between alcohol consumption and risk for gout. ARIC, a 12-year prospective cohort study, identified an association between high levels of alcohol consumption and increased risk for incident gout.19
Studies have also identified dietary factors that reduce the risk for gout or lower serum urate levels. The 2011 systematic review by Singh found that consumption of dairy products and caffeine-containing beverages was associated with a decreased risk for gout.8 Analyzing data from the Nurses' Health Study, Choi and colleagues also found that increasing coffee consumption was associated with a dose-dependent decrease in the risk for gout among women.20 A 2011 SR by Juraschek and colleagues reviewed 13 trials on the effects of administration of vitamin C supplements on serum urate.21 These trials enrolled a total of 556 participants, the median dosage of vitamin C was 500mg/day, trial size ranged from 8–184 participants, and the median study duration was 30 days. Pretreatment serum urate ranged from 2.9 to 7mg/dL. The pooled decrease in serum urate compared with placebo was a significant -0.35mg/dl (95% confidence interval -0.66, -0.03 [P=0.032]). Trials showed significant heterogeneity.
Risk for gout and gout-related outcomes have also been associated with obesity, body mass index, and weight loss. The systematic review by Singh found an association between low BMI and decreased risk for gout8, and a 2014 systematic review that included 10 prospective studies found an association between increasing BMI and risk for gout.22 The MRFIT trial, a prospective cohort study of U.S. men at increased risk for CVD found that weight loss was associated with decreased serum urate although less effective than ULT.23 A recent RCT, the Dietary Intervention Randomized Controlled Trial (DIRECT), found that among 74 overweight and obese participants, a 6-month high-protein, low carbohydrate and low calorie diet resulted in significant weight loss and significant decrease in serum urate levels (0.8mg/dL, p<0.0001); among 18 whose baseline sUA was over 7mg/dL, 61 percent reached the target sUA level.24
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 UA (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 1 lists the drugs used to treat gout and notes the ones covered in this systematic review.
Table 1
Pharmacologic agents used in the treatment of gout.
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;25-27 these agents 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.
Issues of Concern for Management of Gout in Primary Care Settings
The treatment of gout has spawned a proliferation of evidence-based guidelines,28-34 including a recently completed set of guidelines by the American College of Rheumatology (ACR) that consider the treatment of both acute gout and hyperuricemia associated with chronic gout.31,32
However, the majority of individuals with gout are initially seen, diagnosed, and treated in primary care or emergent care settings and may continue to receive their care in these settings. Therefore primary care physicians (PCPs) and emergency physicians need to be well-positioned to diagnose early-stage gout and implement management strategies. It is established that specialists and generalists systematically rate the benefits and harms of treatment differently,35 and in some instances, guidelines on the same clinical topic developed by specialists have had somewhat different recommendations than those developed by generalists.36 Therefore, a new guideline, developed mainly by primary care practitioners and focused on primary care practice, is warranted. This review is intended to provide the evidence for such a guideline.
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. AHRQ assigned this report to the Southern CA Evidence-based Practice Center (HHSA290201200006I). A protocol for the review was accepted and publicly posted on the AHRQ Web site on November 3, 2014 at http://effectivehealthcare.ahrq.gov/ehc/products/564/1992/Gout-managment-protocol-141103.pdf. The protocol was approved by the AHRQ Center for Evidence and Practice Improvement.
Key Questions
The 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
- In patients with acute gout, what are the benefits and harms of different pharmacological therapies?
- Does effectiveness (benefits and harms) differ according to patient baseline demographic characteristics and co-morbid conditions (including renal function)?
- 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
- 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])?
- 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
- 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)?
- 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?
- What is the effect of dietary modification in combination with pharmacologic therapy?
Key Question 4. Treatment Monitoring of Patients with Gout
- 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?
- 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
- urate lowering therapy?
- anti-inflammatory prophylaxis against acute gout attack for patients on urate lowering therapy after an acute gout attack?
Organization of This Report
The remainder of this report presents the methods used to conduct the literature searches, data abstraction, and analysis for this review; the results of the literature searches, organized by KQ; the conclusions; and a discussion of the findings within the context of what is already known, the limitations of the review and the literature, and suggestions for future research.
- Introduction - Management of GoutIntroduction - Management of Gout
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