H. Ralph Schumacher, Jr, MD

A serum urate level greater than approximately 6.8 mg/dL, the saturation point of urate in biological fluids, is the underlying cause of gout. Hyperuricemia, along with other factors (detailed below), over time can result in the deposition of monosodium urate crystals into the joints. Gouty attacks are thought to occur by the abrupt release of these crystals into the joint space, where they may initiate an acute inflammatory reaction recognized as acute gouty arthritis. The acute attack is self-limited, but crystals remain in the joint and low-grade, often subclinical, inflammation persists even between acute attacks. Although acute attacks can be treated with anti-inflammatory medications, the underlying cause of the disease can be treated only by lowering the serum urate level.

CRYSTAL DEPOSITION AND THE DEVELOPMENT OF GOUT

Asymptomatic hyperuricemia is not a disease but rather is the underlying factor that can predispose to gout. A serum urate level of approximately 6.8 mg/dL is the concentration at which monosodium urate crystals begin to precipitate.^1,2 Although this level is based on in vitro studies, it suggests a reasonable biological threshold for clinicians assessing patients for hyperuricemia. It should be noted that there are often no manifestations of gout during an extended period of hyperuricemia even though urate crystals are beginning to deposit into joints. The higher the serum urate level, the more likely that crystals will deposit into joints.

Predisposition is not causation

In the Normative Aging Study, 22% of men who had serum urate levels greater than 9 mg/dL developed gout during a 5-year period—a much higher rate than among men with serum urate levels less than 9 mg/dL.³ Nevertheless, a full 78% of the men in this study with serum urate levels greater than 9 mg/dL did not develop gout over the 5-year period, illustrating that while hyperuricemia predisposes to gout, it does not automatically cause gout.

Contributing factors beyond serum urate

Other factors, when combined with hyperuricemia, contribute to crystal deposition and the development of gout.

Trauma or irritation. Patients with hyperuricemia tend to have monosodium urate crystal deposition at sites of trauma or irritation. The first metatarsophalangeal joint is often affected, at least in part because it is a site of mechanical stress. Likewise, mechanical irritation from leaning on the elbow may cause crystals to deposit in the olecranon bursa.

Lower temperatures favor crystal deposition,^1,4 which may explain why the helix of the ear and the foot are often sites of crystal deposition and tophus development. Both temperature and mechanical effects probably play a role in crystal deposition, however, as gouty attacks tend to occur at the first metatarsophalangeal joint, not at the interphalangeal joints of the foot, which are at a lower temperature.

Previous disease. Crystals also deposit with an increased incidence in previously diseased joints. The Heberden node is a good example.⁵ A patient with osteoarthritis in the fingers may experience dramatically increased pain and swelling because of a gout flare superimposed on an osteoarthritic joint.

 

 

ACUTE GOUTY ARTHRITIS

In some patients, the deposited monosodium urate crystals will be released into the joint space and cause the dramatic acute inflammatory response of acute gouty arthritis. Crystals are believed to be released either by some metabolic change, such as an increase or decrease in serum urate level, or by mechanical trauma. In the joint space, synovial lining cells appear to be the first to phagocytize the crystals.⁶ This sets into motion the formation of a complex called the inflammasome, which releases IL-1 beta, one of the most important mediators of the acute attack.⁷ It stimulates the release of chemokines, other cytokines, prostaglandins, and a variety of other proinflammatory molecules.⁸ The chemokines attract neutrophils into the synovial tissue and the synovial fluid. Neutrophil influx into the joint is a key feature of an acute attack of gout (Figure 1).

Gout flares may resolve spontaneously

Clinicians should be aware that gout attacks initially subside spontaneously.⁹ Because acute attacks of gout typically resolve with or without treatment, especially early in the course of the disease,¹⁰ it can be difficult to evaluate which treatments actually are effective against acute attacks.

A number of factors have been identified to explain how inflammation in acute attacks can be spontaneously suppressed. Crystals may dissolve or become sequestered in the tissue. Monocytes mature into macrophages, changing their responsiveness to urate crystals, and can begin to produce anti-inflammatory cytokines. In addition, some proteins that exude into the joint space with the attack, such as apolipoprotein B, can coat the crystals and reduce their inflammatory properties.¹¹

Crystals persist during intercritical periods

Following an acute attack, the symptoms of gouty arthritis may be gone, but the crystals are still present in the joint. Therefore, the patient remains at risk for continued flares and progressive disease.¹² The crystals that remain in the joint are often associated with a low-grade persistent inflammation.¹³ It is not known why these crystals that remain in the joint fluid between attacks, some of which are phagocytized by white cells, do not initiate the whole cascade of inflammation. The reason may be related to the number of crystals present, their protein coating, or the nature of the resident synovial cells. Crystals may also persist as micro-tophi in the synovium (Figure 2). The key point is that low-grade inflammation persists and crystals remain in the joint, which can lead to progressive disease.¹⁴

ADVANCED GOUT

Clinicians treating patients with gout need to prevent the development of chronic, destructive arthritis and the overt, large tophaceous deposits of advanced gout. Over time, even in the absence of flares, deposited crystals and inflammation can lead to the development of clinically evident joint damage and erosions that can be seen on radiographs (Figure 3) or magnetic resonance imaging.¹⁵

INTERVENTIONS MUST NORMALIZE URATE LEVEL

Acute gout attacks can be treated with anti-inflammatory drugs, but the disease can and often will continue to progress unless the serum urate level is normalized. Two studies of patients whose serum urate levels were successfully reduced to less than 6 mg/dL showed that crystals began to be depleted from the patients’ joint fluid, which should ultimately prevent the risk of progressive gouty arthritis.^12,16 Perez-Ruiz and colleagues have shown that tophi can be dissolved by decreasing the serum urate level.¹⁷ When tophi are present, aiming for even lower levels of serum urate, such as 4 to 5 mg/dL, may help to promote more rapid dissolution of crystals.¹⁷

A serum urate level greater than approximately 6.8 mg/dL, the saturation point of urate in biological fluids, is the underlying cause of gout. Hyperuricemia, along with other factors (detailed below), over time can result in the deposition of monosodium urate crystals into the joints. Gouty attacks are thought to occur by the abrupt release of these crystals into the joint space, where they may initiate an acute inflammatory reaction recognized as acute gouty arthritis. The acute attack is self-limited, but crystals remain in the joint and low-grade, often subclinical, inflammation persists even between acute attacks. Although acute attacks can be treated with anti-inflammatory medications, the underlying cause of the disease can be treated only by lowering the serum urate level.

CRYSTAL DEPOSITION AND THE DEVELOPMENT OF GOUT

Asymptomatic hyperuricemia is not a disease but rather is the underlying factor that can predispose to gout. A serum urate level of approximately 6.8 mg/dL is the concentration at which monosodium urate crystals begin to precipitate.^1,2 Although this level is based on in vitro studies, it suggests a reasonable biological threshold for clinicians assessing patients for hyperuricemia. It should be noted that there are often no manifestations of gout during an extended period of hyperuricemia even though urate crystals are beginning to deposit into joints. The higher the serum urate level, the more likely that crystals will deposit into joints.

Predisposition is not causation

In the Normative Aging Study, 22% of men who had serum urate levels greater than 9 mg/dL developed gout during a 5-year period—a much higher rate than among men with serum urate levels less than 9 mg/dL.³ Nevertheless, a full 78% of the men in this study with serum urate levels greater than 9 mg/dL did not develop gout over the 5-year period, illustrating that while hyperuricemia predisposes to gout, it does not automatically cause gout.

Contributing factors beyond serum urate

Other factors, when combined with hyperuricemia, contribute to crystal deposition and the development of gout.

Trauma or irritation. Patients with hyperuricemia tend to have monosodium urate crystal deposition at sites of trauma or irritation. The first metatarsophalangeal joint is often affected, at least in part because it is a site of mechanical stress. Likewise, mechanical irritation from leaning on the elbow may cause crystals to deposit in the olecranon bursa.

Lower temperatures favor crystal deposition,^1,4 which may explain why the helix of the ear and the foot are often sites of crystal deposition and tophus development. Both temperature and mechanical effects probably play a role in crystal deposition, however, as gouty attacks tend to occur at the first metatarsophalangeal joint, not at the interphalangeal joints of the foot, which are at a lower temperature.

Previous disease. Crystals also deposit with an increased incidence in previously diseased joints. The Heberden node is a good example.⁵ A patient with osteoarthritis in the fingers may experience dramatically increased pain and swelling because of a gout flare superimposed on an osteoarthritic joint.

 

 

ACUTE GOUTY ARTHRITIS

In some patients, the deposited monosodium urate crystals will be released into the joint space and cause the dramatic acute inflammatory response of acute gouty arthritis. Crystals are believed to be released either by some metabolic change, such as an increase or decrease in serum urate level, or by mechanical trauma. In the joint space, synovial lining cells appear to be the first to phagocytize the crystals.⁶ This sets into motion the formation of a complex called the inflammasome, which releases IL-1 beta, one of the most important mediators of the acute attack.⁷ It stimulates the release of chemokines, other cytokines, prostaglandins, and a variety of other proinflammatory molecules.⁸ The chemokines attract neutrophils into the synovial tissue and the synovial fluid. Neutrophil influx into the joint is a key feature of an acute attack of gout (Figure 1).

Gout flares may resolve spontaneously

Clinicians should be aware that gout attacks initially subside spontaneously.⁹ Because acute attacks of gout typically resolve with or without treatment, especially early in the course of the disease,¹⁰ it can be difficult to evaluate which treatments actually are effective against acute attacks.

A number of factors have been identified to explain how inflammation in acute attacks can be spontaneously suppressed. Crystals may dissolve or become sequestered in the tissue. Monocytes mature into macrophages, changing their responsiveness to urate crystals, and can begin to produce anti-inflammatory cytokines. In addition, some proteins that exude into the joint space with the attack, such as apolipoprotein B, can coat the crystals and reduce their inflammatory properties.¹¹

Crystals persist during intercritical periods

Following an acute attack, the symptoms of gouty arthritis may be gone, but the crystals are still present in the joint. Therefore, the patient remains at risk for continued flares and progressive disease.¹² The crystals that remain in the joint are often associated with a low-grade persistent inflammation.¹³ It is not known why these crystals that remain in the joint fluid between attacks, some of which are phagocytized by white cells, do not initiate the whole cascade of inflammation. The reason may be related to the number of crystals present, their protein coating, or the nature of the resident synovial cells. Crystals may also persist as micro-tophi in the synovium (Figure 2). The key point is that low-grade inflammation persists and crystals remain in the joint, which can lead to progressive disease.¹⁴

ADVANCED GOUT

Clinicians treating patients with gout need to prevent the development of chronic, destructive arthritis and the overt, large tophaceous deposits of advanced gout. Over time, even in the absence of flares, deposited crystals and inflammation can lead to the development of clinically evident joint damage and erosions that can be seen on radiographs (Figure 3) or magnetic resonance imaging.¹⁵

INTERVENTIONS MUST NORMALIZE URATE LEVEL

Acute gout attacks can be treated with anti-inflammatory drugs, but the disease can and often will continue to progress unless the serum urate level is normalized. Two studies of patients whose serum urate levels were successfully reduced to less than 6 mg/dL showed that crystals began to be depleted from the patients’ joint fluid, which should ultimately prevent the risk of progressive gouty arthritis.^12,16 Perez-Ruiz and colleagues have shown that tophi can be dissolved by decreasing the serum urate level.¹⁷ When tophi are present, aiming for even lower levels of serum urate, such as 4 to 5 mg/dL, may help to promote more rapid dissolution of crystals.¹⁷

A serum urate level greater than approximately 6.8 mg/dL, the saturation point of urate in biological fluids, is the underlying cause of gout. Hyperuricemia, along with other factors (detailed below), over time can result in the deposition of monosodium urate crystals into the joints. Gouty attacks are thought to occur by the abrupt release of these crystals into the joint space, where they may initiate an acute inflammatory reaction recognized as acute gouty arthritis. The acute attack is self-limited, but crystals remain in the joint and low-grade, often subclinical, inflammation persists even between acute attacks. Although acute attacks can be treated with anti-inflammatory medications, the underlying cause of the disease can be treated only by lowering the serum urate level.

CRYSTAL DEPOSITION AND THE DEVELOPMENT OF GOUT

Asymptomatic hyperuricemia is not a disease but rather is the underlying factor that can predispose to gout. A serum urate level of approximately 6.8 mg/dL is the concentration at which monosodium urate crystals begin to precipitate.^1,2 Although this level is based on in vitro studies, it suggests a reasonable biological threshold for clinicians assessing patients for hyperuricemia. It should be noted that there are often no manifestations of gout during an extended period of hyperuricemia even though urate crystals are beginning to deposit into joints. The higher the serum urate level, the more likely that crystals will deposit into joints.

Predisposition is not causation

In the Normative Aging Study, 22% of men who had serum urate levels greater than 9 mg/dL developed gout during a 5-year period—a much higher rate than among men with serum urate levels less than 9 mg/dL.³ Nevertheless, a full 78% of the men in this study with serum urate levels greater than 9 mg/dL did not develop gout over the 5-year period, illustrating that while hyperuricemia predisposes to gout, it does not automatically cause gout.

Contributing factors beyond serum urate

Other factors, when combined with hyperuricemia, contribute to crystal deposition and the development of gout.

Trauma or irritation. Patients with hyperuricemia tend to have monosodium urate crystal deposition at sites of trauma or irritation. The first metatarsophalangeal joint is often affected, at least in part because it is a site of mechanical stress. Likewise, mechanical irritation from leaning on the elbow may cause crystals to deposit in the olecranon bursa.

Lower temperatures favor crystal deposition,^1,4 which may explain why the helix of the ear and the foot are often sites of crystal deposition and tophus development. Both temperature and mechanical effects probably play a role in crystal deposition, however, as gouty attacks tend to occur at the first metatarsophalangeal joint, not at the interphalangeal joints of the foot, which are at a lower temperature.

Previous disease. Crystals also deposit with an increased incidence in previously diseased joints. The Heberden node is a good example.⁵ A patient with osteoarthritis in the fingers may experience dramatically increased pain and swelling because of a gout flare superimposed on an osteoarthritic joint.

 

 

ACUTE GOUTY ARTHRITIS

In some patients, the deposited monosodium urate crystals will be released into the joint space and cause the dramatic acute inflammatory response of acute gouty arthritis. Crystals are believed to be released either by some metabolic change, such as an increase or decrease in serum urate level, or by mechanical trauma. In the joint space, synovial lining cells appear to be the first to phagocytize the crystals.⁶ This sets into motion the formation of a complex called the inflammasome, which releases IL-1 beta, one of the most important mediators of the acute attack.⁷ It stimulates the release of chemokines, other cytokines, prostaglandins, and a variety of other proinflammatory molecules.⁸ The chemokines attract neutrophils into the synovial tissue and the synovial fluid. Neutrophil influx into the joint is a key feature of an acute attack of gout (Figure 1).

Gout flares may resolve spontaneously

Clinicians should be aware that gout attacks initially subside spontaneously.⁹ Because acute attacks of gout typically resolve with or without treatment, especially early in the course of the disease,¹⁰ it can be difficult to evaluate which treatments actually are effective against acute attacks.

A number of factors have been identified to explain how inflammation in acute attacks can be spontaneously suppressed. Crystals may dissolve or become sequestered in the tissue. Monocytes mature into macrophages, changing their responsiveness to urate crystals, and can begin to produce anti-inflammatory cytokines. In addition, some proteins that exude into the joint space with the attack, such as apolipoprotein B, can coat the crystals and reduce their inflammatory properties.¹¹

Crystals persist during intercritical periods

Following an acute attack, the symptoms of gouty arthritis may be gone, but the crystals are still present in the joint. Therefore, the patient remains at risk for continued flares and progressive disease.¹² The crystals that remain in the joint are often associated with a low-grade persistent inflammation.¹³ It is not known why these crystals that remain in the joint fluid between attacks, some of which are phagocytized by white cells, do not initiate the whole cascade of inflammation. The reason may be related to the number of crystals present, their protein coating, or the nature of the resident synovial cells. Crystals may also persist as micro-tophi in the synovium (Figure 2). The key point is that low-grade inflammation persists and crystals remain in the joint, which can lead to progressive disease.¹⁴

ADVANCED GOUT

Clinicians treating patients with gout need to prevent the development of chronic, destructive arthritis and the overt, large tophaceous deposits of advanced gout. Over time, even in the absence of flares, deposited crystals and inflammation can lead to the development of clinically evident joint damage and erosions that can be seen on radiographs (Figure 3) or magnetic resonance imaging.¹⁵

INTERVENTIONS MUST NORMALIZE URATE LEVEL

Acute gout attacks can be treated with anti-inflammatory drugs, but the disease can and often will continue to progress unless the serum urate level is normalized. Two studies of patients whose serum urate levels were successfully reduced to less than 6 mg/dL showed that crystals began to be depleted from the patients’ joint fluid, which should ultimately prevent the risk of progressive gouty arthritis.^12,16 Perez-Ruiz and colleagues have shown that tophi can be dissolved by decreasing the serum urate level.¹⁷ When tophi are present, aiming for even lower levels of serum urate, such as 4 to 5 mg/dL, may help to promote more rapid dissolution of crystals.¹⁷

To apropriately manage gout, it is important to distinguish between treatment of acute gout attacks and management of the underlying metabolic defect. While acute attacks are treated with anti-inflammatory agents, the underlying hyperuricemia must be addressed by lowering the serum urate concentration to levels that lead to prevention of acute flares, together with consideration of the contributing role of the patient’s lifestyle factors and comorbidities. This article surveys treatment options for both acute gout attacks and the underlying hyperuricemic state, focusing on considerations to guide therapy selection and optimize prospects for treatment success.

ACUTE GOUTY ARTHRITIS: ANTI-INFLAMMATORY AGENTS AND KEY ISSUES FOR THEIR USE

Acute attacks of gouty arthritis can be treated with any of several anti-inflammatory agents (Table 1). The earlier anti-inflammatory treatment is started, the more rapidly the acute flare will subside. Adequate dosing and duration is important; treatment should be continued until the flare has resolved and then reduced in tapered doses for at least 2 to 3 days after all overt signs of inflammation are gone.

One of the most important considerations in selecting an anti-inflammatory medication is how the patient’s comorbidities, such as renal disease, or concurrent medications may influence the choice of agent, as outlined in Table 1.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

A number of NSAIDs are available to treat acute flares of gout.^1–3 When used at a full anti-inflammatory dose, all NSAIDs appear to be equally effective.

NSAIDs must be used cautiously in patients who have any of a number of comorbid conditions, as detailed in Table 1. If a patient is otherwise healthy—without significant renal, cardiovascular, or gastrointestinal disease—and has no history of aspirin allergy, NSAIDs are the treatment of choice for acute gout attacks. Use of a proton pump inhibitor can improve gastrointestinal tolerance of NSAIDs and reduce the likelihood of gastric bleeding but may not avoid other concerns. Indomethacin can cause headache or even confusion, particularly in the elderly.

Colchicine

Colchicine can be an effective alternative for acute therapy.^4,5 If a patient with previously documented gout can be coached to begin colchicine at the first hint of a gout attack, a full-blown attack often can be prevented. A colchicine regimen of 0.5 or 0.6 mg 3 times daily, although not well studied, may be effective while limiting the diarrhea, nausea, and vomiting that is predictable with hourly colchicine dosing.^6,7 Colchicine must be used cautiously in patients with renal or liver disease and is contraindicated in patients undergoing dialysis.⁸

Corticosteroids

Systemic corticosteroids are often used for polyarticular gout or in patients with contraindications to NSAIDs or colchicine.⁹ When they are used in diabetic patients, glycemic control must be monitored, and an increased insulin dose can be prescribed temporarily until glucose levels normalize.

Corticosteroids may also be injected directly into the joint, as this approach offers reduced risks compared with oral administration. Direct injection is especially useful in patients with attacks that involve only one or two joints.

TREATING THE UNDERLYING HYPERURICEMIA THROUGH URATE-LOWERING STRATEGIES

Terminating the acute flare manages gout symptoms but does not treat the underlying disease. Crystals often remain in the joint after flares have resolved. Addressing the underlying metabolic condition requires lowering serum urate levels, which can deplete crystals and reduce or prevent gout flares.

The goals of urate-lowering therapy are to reduce serum urate levels to less than 6 mg/dL in order to mobilize and deplete crystals with minimal toxicity.¹⁰

Role of lifestyle interventions

As discussed by Weaver earlier in this supplement, obesity and certain patterns of food and alcohol consumption can increase the risk of developing hyperuricemia and gout. In addition to weight loss, dietary changes.such as reducing intake of animal purines, high-fructose sweeteners, and alcohol, and increasing intake of vitamin C or bing cherries.may lower serum urate levels modestly (ie, by 1 or 2 mg/dL).^11–15 While lifestyle interventions may be all that is needed in some patients with early mild gout, such interventions generally do not replace the need for urate-lowering drug therapy in cases of existing gout. Accordingly, this discussion focuses on medications used to treat hyperuricemia in the United States: the xanthine oxidase inhibitor allopurinol and the uricosuric agent probenecid.

Initiating urate-lowering drug therapy

Chronic therapy should be discussed with the patient early in the course of the disease. Treatment recommendations need to be individualized based on the patient’s overall health, comorbidities, and willingness to adhere to chronic treatment.

Initiation of urate-lowering therapy is appropriate to consider after the acute attack has fully resolved and the patient has been stable for 1 to 2 weeks. If a patient’s serum urate level is very high (eg, > 10 mg/dL), urate-lowering therapy may be initiated even after a single attack, as progression is more likely to occur with higher levels. Treatment should be initiated long before tophi or persistent joint damage develop. If the patient already has objective radiographic evidence of gouty changes in the joints, or if tophi or nephrolithiasis are present when the patient is first seen, urate-lowering therapy should be started.

Concurrent low-dose anti-inflammatory prophylaxis

Abrupt decreases (or increases) in serum urate levels may precipitate gout flares. For this reason, anti-inflammatory prophylaxis should be used when urate-lowering therapy is initiated, as it can quickly reduce serum urate levels. Colchicine (0.6 mg once or twice daily)⁸ or NSAIDs (eg, naproxen 250 mg/day) prescribed at lower than full anti-inflammatory doses may be used to prevent flares in this setting. When using long-term colchicine in a patient with renal disease, lower doses must be used and the patient should be monitored closely for reversible axonal neuromyopathy and vacuolar myopathy or rhabdomyolysis; the latter complication may be more frequent in patients taking concurrent statin or macrolide therapy. There are no controlled studies on the benefits and safety of prophylactic NSAID use in gouty patients with comorbidities.

Borstad et al documented in a placebo-controlled study that colchicine prophylaxis at the time of allopurinol initiation reduces flares but does not completely abolish them.¹⁶ From 0 to 3 months after therapy initiation, the mean number of flares was 0.57 in patients who received colchicine versus 1.91 in patients who received placebo (P = .022); from 3 to 6 months after initiation, the mean number of flares was 0 versus 1.05 in the respective patient groups (P = .033).¹⁶

Depending on the body’s urate load, it may take many months to deplete crystals. There is evidence that prophylaxis should be used for at least 3 to 6 months to reduce the risk of mobilization flares.¹⁶ Patients should be warned during this time that gout flares may still occur and should be treated promptly. Prophylaxis should continue longer in patients with tophi, often until the tophi have resolved.

 

 

Allopurinol

The xanthine oxidase inhibitor allopurinol works by blocking production of uric acid and can be used in any patient with gout (Table 2). When initiating allopurinol, the safest option is to start all patients on 100 mg/day and increase the dose gradually to attempt to lower the risk of mobilization flares. Achieving full therapeutic benefit, including a reduction in flares, frequently requires doses greater than the commonly used 300 mg/day.¹⁷ The serum urate level should be monitored every 2 weeks during dose escalation until the level is less than 6 mg/dL. Once a stable level is established, the serum urate can be checked once or twice a year to ensure that therapeutic concentrations are maintained.

The rare but potentially fatal hypersensitivity syndrome is a concern with allopurinol. If a rash develops in a patient taking allopurinol, the drug should be discontinued, as rash can be a precursor of severe systemic hypersensitivity.

Renal function must be considered in allopurinol dosing, and treatment should always be initiated at lower doses in patients with renal disease.¹⁸ However, recent reports indicate that allopurinol doses can be gradually and safely increased to an effective level that achieves a serum urate concentration of less than 6 mg/dL even in patients with reduced kidney function.^19,20

Uricosurics

The uricosuric agent probenecid works by increasing the urinary excretion of urate.¹⁰ Probenecid is commonly dosed at 500 mg twice daily, with a maximum daily dose of 2 g, in an attempt to reach the target serum urate level. Probenecid is unlikely to be effective if the patient’s serum creatinine is greater than 2 mg/dL.²¹

When a uricosuric agent is used, a 24-hour urine urate measurement must be taken to identify and exclude urate overproducers (patients with more than 800 to 1,000 mg of uric acid in a good 24-hour collection), as such patients are at risk for uric acid kidney stones. Additionally, aspirin interferes with probenecid’s effect on the renal tubules. The ideal candidate for uricosuric therapy has good kidney function, is not a urate overproducer, and is willing to drink 8 glasses of water a day to minimize the risk of kidney stones (Table 2).

Evidence supporting urate targets and continuous maintenance of urate reductions

If a serum urate level of less than 6 mg/dL is achieved and maintained, gout flares will be reduced and crystals can be depleted from inside the joint.^22–25 Additionally, the size of tophi can be reduced and their recurrence prevented.^26–28 Serum urate levels below 4 mg/dL can result in more rapid dissolution of tophi.²⁶

Reprinted, with permission, from Journal of Rheumatology (Bull PW, Scott JT. J Rheumatol 1989; 16:1246–1248).

Urate-lowering therapy with allopurinol or probenecid is generally a lifelong commitment. Intermittent therapy or cessation of therapy can lead to recurrent attacks.^21,28,29 In a randomized trial examining outcomes of continuous versus intermittent urate-lowering therapy with allopurinol, gout attacks were eliminated after about 2 years of therapy in patients who continuously received allopurinol, whereas they continued to recur beyond 2 years in patients who received allopurinol intermittently (ie, due to the way it was prescribed or nonadherence) (Figure 1).²⁹

Patient commitment and education are essential

No treatment plan will succeed without the commitment of the patient, so discussion to determine the patient’s willingness to commit to lifetime therapy is warranted. A number of surveys have shown that the rate of continued use of allopurinol after it is initially prescribed is less than 50%.¹⁷ If the physician or nurse monitors adherence, however, treatment is more likely to be successful.³⁰

Patients need more education about gout, as education may improve adherence and treatment success. Patient education material is available from the Arthritis Foundation (www.arthritis.org/disease-center.php) and the Gout & Uric Acid Education Society (www.gouteducation.org).

CONCLUSION

A comprehensive treatment strategy is critical to ensure ideal gout therapy. Acute flares should be addressed as rapidly as possible with an anti-inflammatory agent selected on the basis of the patient’s comorbidities and other medications. Most patients require chronic urate-lowering therapy to deplete crystals from joints and prevent flares. Initiation of urate-lowering therapy should be considered early in the disease course, following resolution of the acute attack. Low-dose anti-inflammatory prophylaxis should be initiated when any urate-lowering therapy is started. Regular monitoring of serum urate will ensure effective dosing to achieve a target serum urate level of less than 6 mg/dL. Once urate deposits are depleted, acute flares should cease.

To apropriately manage gout, it is important to distinguish between treatment of acute gout attacks and management of the underlying metabolic defect. While acute attacks are treated with anti-inflammatory agents, the underlying hyperuricemia must be addressed by lowering the serum urate concentration to levels that lead to prevention of acute flares, together with consideration of the contributing role of the patient’s lifestyle factors and comorbidities. This article surveys treatment options for both acute gout attacks and the underlying hyperuricemic state, focusing on considerations to guide therapy selection and optimize prospects for treatment success.

ACUTE GOUTY ARTHRITIS: ANTI-INFLAMMATORY AGENTS AND KEY ISSUES FOR THEIR USE

Acute attacks of gouty arthritis can be treated with any of several anti-inflammatory agents (Table 1). The earlier anti-inflammatory treatment is started, the more rapidly the acute flare will subside. Adequate dosing and duration is important; treatment should be continued until the flare has resolved and then reduced in tapered doses for at least 2 to 3 days after all overt signs of inflammation are gone.

One of the most important considerations in selecting an anti-inflammatory medication is how the patient’s comorbidities, such as renal disease, or concurrent medications may influence the choice of agent, as outlined in Table 1.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

A number of NSAIDs are available to treat acute flares of gout.^1–3 When used at a full anti-inflammatory dose, all NSAIDs appear to be equally effective.

NSAIDs must be used cautiously in patients who have any of a number of comorbid conditions, as detailed in Table 1. If a patient is otherwise healthy—without significant renal, cardiovascular, or gastrointestinal disease—and has no history of aspirin allergy, NSAIDs are the treatment of choice for acute gout attacks. Use of a proton pump inhibitor can improve gastrointestinal tolerance of NSAIDs and reduce the likelihood of gastric bleeding but may not avoid other concerns. Indomethacin can cause headache or even confusion, particularly in the elderly.

Colchicine

Colchicine can be an effective alternative for acute therapy.^4,5 If a patient with previously documented gout can be coached to begin colchicine at the first hint of a gout attack, a full-blown attack often can be prevented. A colchicine regimen of 0.5 or 0.6 mg 3 times daily, although not well studied, may be effective while limiting the diarrhea, nausea, and vomiting that is predictable with hourly colchicine dosing.^6,7 Colchicine must be used cautiously in patients with renal or liver disease and is contraindicated in patients undergoing dialysis.⁸

Corticosteroids

Systemic corticosteroids are often used for polyarticular gout or in patients with contraindications to NSAIDs or colchicine.⁹ When they are used in diabetic patients, glycemic control must be monitored, and an increased insulin dose can be prescribed temporarily until glucose levels normalize.

Corticosteroids may also be injected directly into the joint, as this approach offers reduced risks compared with oral administration. Direct injection is especially useful in patients with attacks that involve only one or two joints.

TREATING THE UNDERLYING HYPERURICEMIA THROUGH URATE-LOWERING STRATEGIES

Terminating the acute flare manages gout symptoms but does not treat the underlying disease. Crystals often remain in the joint after flares have resolved. Addressing the underlying metabolic condition requires lowering serum urate levels, which can deplete crystals and reduce or prevent gout flares.

The goals of urate-lowering therapy are to reduce serum urate levels to less than 6 mg/dL in order to mobilize and deplete crystals with minimal toxicity.¹⁰

Role of lifestyle interventions

As discussed by Weaver earlier in this supplement, obesity and certain patterns of food and alcohol consumption can increase the risk of developing hyperuricemia and gout. In addition to weight loss, dietary changes.such as reducing intake of animal purines, high-fructose sweeteners, and alcohol, and increasing intake of vitamin C or bing cherries.may lower serum urate levels modestly (ie, by 1 or 2 mg/dL).^11–15 While lifestyle interventions may be all that is needed in some patients with early mild gout, such interventions generally do not replace the need for urate-lowering drug therapy in cases of existing gout. Accordingly, this discussion focuses on medications used to treat hyperuricemia in the United States: the xanthine oxidase inhibitor allopurinol and the uricosuric agent probenecid.

Initiating urate-lowering drug therapy

Chronic therapy should be discussed with the patient early in the course of the disease. Treatment recommendations need to be individualized based on the patient’s overall health, comorbidities, and willingness to adhere to chronic treatment.

Initiation of urate-lowering therapy is appropriate to consider after the acute attack has fully resolved and the patient has been stable for 1 to 2 weeks. If a patient’s serum urate level is very high (eg, > 10 mg/dL), urate-lowering therapy may be initiated even after a single attack, as progression is more likely to occur with higher levels. Treatment should be initiated long before tophi or persistent joint damage develop. If the patient already has objective radiographic evidence of gouty changes in the joints, or if tophi or nephrolithiasis are present when the patient is first seen, urate-lowering therapy should be started.

Concurrent low-dose anti-inflammatory prophylaxis

Abrupt decreases (or increases) in serum urate levels may precipitate gout flares. For this reason, anti-inflammatory prophylaxis should be used when urate-lowering therapy is initiated, as it can quickly reduce serum urate levels. Colchicine (0.6 mg once or twice daily)⁸ or NSAIDs (eg, naproxen 250 mg/day) prescribed at lower than full anti-inflammatory doses may be used to prevent flares in this setting. When using long-term colchicine in a patient with renal disease, lower doses must be used and the patient should be monitored closely for reversible axonal neuromyopathy and vacuolar myopathy or rhabdomyolysis; the latter complication may be more frequent in patients taking concurrent statin or macrolide therapy. There are no controlled studies on the benefits and safety of prophylactic NSAID use in gouty patients with comorbidities.

Borstad et al documented in a placebo-controlled study that colchicine prophylaxis at the time of allopurinol initiation reduces flares but does not completely abolish them.¹⁶ From 0 to 3 months after therapy initiation, the mean number of flares was 0.57 in patients who received colchicine versus 1.91 in patients who received placebo (P = .022); from 3 to 6 months after initiation, the mean number of flares was 0 versus 1.05 in the respective patient groups (P = .033).¹⁶

Depending on the body’s urate load, it may take many months to deplete crystals. There is evidence that prophylaxis should be used for at least 3 to 6 months to reduce the risk of mobilization flares.¹⁶ Patients should be warned during this time that gout flares may still occur and should be treated promptly. Prophylaxis should continue longer in patients with tophi, often until the tophi have resolved.

 

 

Allopurinol

The xanthine oxidase inhibitor allopurinol works by blocking production of uric acid and can be used in any patient with gout (Table 2). When initiating allopurinol, the safest option is to start all patients on 100 mg/day and increase the dose gradually to attempt to lower the risk of mobilization flares. Achieving full therapeutic benefit, including a reduction in flares, frequently requires doses greater than the commonly used 300 mg/day.¹⁷ The serum urate level should be monitored every 2 weeks during dose escalation until the level is less than 6 mg/dL. Once a stable level is established, the serum urate can be checked once or twice a year to ensure that therapeutic concentrations are maintained.

The rare but potentially fatal hypersensitivity syndrome is a concern with allopurinol. If a rash develops in a patient taking allopurinol, the drug should be discontinued, as rash can be a precursor of severe systemic hypersensitivity.

Renal function must be considered in allopurinol dosing, and treatment should always be initiated at lower doses in patients with renal disease.¹⁸ However, recent reports indicate that allopurinol doses can be gradually and safely increased to an effective level that achieves a serum urate concentration of less than 6 mg/dL even in patients with reduced kidney function.^19,20

Uricosurics

The uricosuric agent probenecid works by increasing the urinary excretion of urate.¹⁰ Probenecid is commonly dosed at 500 mg twice daily, with a maximum daily dose of 2 g, in an attempt to reach the target serum urate level. Probenecid is unlikely to be effective if the patient’s serum creatinine is greater than 2 mg/dL.²¹

When a uricosuric agent is used, a 24-hour urine urate measurement must be taken to identify and exclude urate overproducers (patients with more than 800 to 1,000 mg of uric acid in a good 24-hour collection), as such patients are at risk for uric acid kidney stones. Additionally, aspirin interferes with probenecid’s effect on the renal tubules. The ideal candidate for uricosuric therapy has good kidney function, is not a urate overproducer, and is willing to drink 8 glasses of water a day to minimize the risk of kidney stones (Table 2).

Evidence supporting urate targets and continuous maintenance of urate reductions

If a serum urate level of less than 6 mg/dL is achieved and maintained, gout flares will be reduced and crystals can be depleted from inside the joint.^22–25 Additionally, the size of tophi can be reduced and their recurrence prevented.^26–28 Serum urate levels below 4 mg/dL can result in more rapid dissolution of tophi.²⁶

Reprinted, with permission, from Journal of Rheumatology (Bull PW, Scott JT. J Rheumatol 1989; 16:1246–1248).

Urate-lowering therapy with allopurinol or probenecid is generally a lifelong commitment. Intermittent therapy or cessation of therapy can lead to recurrent attacks.^21,28,29 In a randomized trial examining outcomes of continuous versus intermittent urate-lowering therapy with allopurinol, gout attacks were eliminated after about 2 years of therapy in patients who continuously received allopurinol, whereas they continued to recur beyond 2 years in patients who received allopurinol intermittently (ie, due to the way it was prescribed or nonadherence) (Figure 1).²⁹

Patient commitment and education are essential

No treatment plan will succeed without the commitment of the patient, so discussion to determine the patient’s willingness to commit to lifetime therapy is warranted. A number of surveys have shown that the rate of continued use of allopurinol after it is initially prescribed is less than 50%.¹⁷ If the physician or nurse monitors adherence, however, treatment is more likely to be successful.³⁰

Patients need more education about gout, as education may improve adherence and treatment success. Patient education material is available from the Arthritis Foundation (www.arthritis.org/disease-center.php) and the Gout & Uric Acid Education Society (www.gouteducation.org).

CONCLUSION

A comprehensive treatment strategy is critical to ensure ideal gout therapy. Acute flares should be addressed as rapidly as possible with an anti-inflammatory agent selected on the basis of the patient’s comorbidities and other medications. Most patients require chronic urate-lowering therapy to deplete crystals from joints and prevent flares. Initiation of urate-lowering therapy should be considered early in the disease course, following resolution of the acute attack. Low-dose anti-inflammatory prophylaxis should be initiated when any urate-lowering therapy is started. Regular monitoring of serum urate will ensure effective dosing to achieve a target serum urate level of less than 6 mg/dL. Once urate deposits are depleted, acute flares should cease.

To apropriately manage gout, it is important to distinguish between treatment of acute gout attacks and management of the underlying metabolic defect. While acute attacks are treated with anti-inflammatory agents, the underlying hyperuricemia must be addressed by lowering the serum urate concentration to levels that lead to prevention of acute flares, together with consideration of the contributing role of the patient’s lifestyle factors and comorbidities. This article surveys treatment options for both acute gout attacks and the underlying hyperuricemic state, focusing on considerations to guide therapy selection and optimize prospects for treatment success.

ACUTE GOUTY ARTHRITIS: ANTI-INFLAMMATORY AGENTS AND KEY ISSUES FOR THEIR USE

Acute attacks of gouty arthritis can be treated with any of several anti-inflammatory agents (Table 1). The earlier anti-inflammatory treatment is started, the more rapidly the acute flare will subside. Adequate dosing and duration is important; treatment should be continued until the flare has resolved and then reduced in tapered doses for at least 2 to 3 days after all overt signs of inflammation are gone.

One of the most important considerations in selecting an anti-inflammatory medication is how the patient’s comorbidities, such as renal disease, or concurrent medications may influence the choice of agent, as outlined in Table 1.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

A number of NSAIDs are available to treat acute flares of gout.^1–3 When used at a full anti-inflammatory dose, all NSAIDs appear to be equally effective.

NSAIDs must be used cautiously in patients who have any of a number of comorbid conditions, as detailed in Table 1. If a patient is otherwise healthy—without significant renal, cardiovascular, or gastrointestinal disease—and has no history of aspirin allergy, NSAIDs are the treatment of choice for acute gout attacks. Use of a proton pump inhibitor can improve gastrointestinal tolerance of NSAIDs and reduce the likelihood of gastric bleeding but may not avoid other concerns. Indomethacin can cause headache or even confusion, particularly in the elderly.

Colchicine

Colchicine can be an effective alternative for acute therapy.^4,5 If a patient with previously documented gout can be coached to begin colchicine at the first hint of a gout attack, a full-blown attack often can be prevented. A colchicine regimen of 0.5 or 0.6 mg 3 times daily, although not well studied, may be effective while limiting the diarrhea, nausea, and vomiting that is predictable with hourly colchicine dosing.^6,7 Colchicine must be used cautiously in patients with renal or liver disease and is contraindicated in patients undergoing dialysis.⁸

Corticosteroids

Systemic corticosteroids are often used for polyarticular gout or in patients with contraindications to NSAIDs or colchicine.⁹ When they are used in diabetic patients, glycemic control must be monitored, and an increased insulin dose can be prescribed temporarily until glucose levels normalize.

Corticosteroids may also be injected directly into the joint, as this approach offers reduced risks compared with oral administration. Direct injection is especially useful in patients with attacks that involve only one or two joints.

TREATING THE UNDERLYING HYPERURICEMIA THROUGH URATE-LOWERING STRATEGIES

Terminating the acute flare manages gout symptoms but does not treat the underlying disease. Crystals often remain in the joint after flares have resolved. Addressing the underlying metabolic condition requires lowering serum urate levels, which can deplete crystals and reduce or prevent gout flares.

The goals of urate-lowering therapy are to reduce serum urate levels to less than 6 mg/dL in order to mobilize and deplete crystals with minimal toxicity.¹⁰

Role of lifestyle interventions

As discussed by Weaver earlier in this supplement, obesity and certain patterns of food and alcohol consumption can increase the risk of developing hyperuricemia and gout. In addition to weight loss, dietary changes.such as reducing intake of animal purines, high-fructose sweeteners, and alcohol, and increasing intake of vitamin C or bing cherries.may lower serum urate levels modestly (ie, by 1 or 2 mg/dL).^11–15 While lifestyle interventions may be all that is needed in some patients with early mild gout, such interventions generally do not replace the need for urate-lowering drug therapy in cases of existing gout. Accordingly, this discussion focuses on medications used to treat hyperuricemia in the United States: the xanthine oxidase inhibitor allopurinol and the uricosuric agent probenecid.

Initiating urate-lowering drug therapy

Chronic therapy should be discussed with the patient early in the course of the disease. Treatment recommendations need to be individualized based on the patient’s overall health, comorbidities, and willingness to adhere to chronic treatment.

Initiation of urate-lowering therapy is appropriate to consider after the acute attack has fully resolved and the patient has been stable for 1 to 2 weeks. If a patient’s serum urate level is very high (eg, > 10 mg/dL), urate-lowering therapy may be initiated even after a single attack, as progression is more likely to occur with higher levels. Treatment should be initiated long before tophi or persistent joint damage develop. If the patient already has objective radiographic evidence of gouty changes in the joints, or if tophi or nephrolithiasis are present when the patient is first seen, urate-lowering therapy should be started.

Concurrent low-dose anti-inflammatory prophylaxis

Abrupt decreases (or increases) in serum urate levels may precipitate gout flares. For this reason, anti-inflammatory prophylaxis should be used when urate-lowering therapy is initiated, as it can quickly reduce serum urate levels. Colchicine (0.6 mg once or twice daily)⁸ or NSAIDs (eg, naproxen 250 mg/day) prescribed at lower than full anti-inflammatory doses may be used to prevent flares in this setting. When using long-term colchicine in a patient with renal disease, lower doses must be used and the patient should be monitored closely for reversible axonal neuromyopathy and vacuolar myopathy or rhabdomyolysis; the latter complication may be more frequent in patients taking concurrent statin or macrolide therapy. There are no controlled studies on the benefits and safety of prophylactic NSAID use in gouty patients with comorbidities.

Borstad et al documented in a placebo-controlled study that colchicine prophylaxis at the time of allopurinol initiation reduces flares but does not completely abolish them.¹⁶ From 0 to 3 months after therapy initiation, the mean number of flares was 0.57 in patients who received colchicine versus 1.91 in patients who received placebo (P = .022); from 3 to 6 months after initiation, the mean number of flares was 0 versus 1.05 in the respective patient groups (P = .033).¹⁶

Depending on the body’s urate load, it may take many months to deplete crystals. There is evidence that prophylaxis should be used for at least 3 to 6 months to reduce the risk of mobilization flares.¹⁶ Patients should be warned during this time that gout flares may still occur and should be treated promptly. Prophylaxis should continue longer in patients with tophi, often until the tophi have resolved.

 

 

Allopurinol

The xanthine oxidase inhibitor allopurinol works by blocking production of uric acid and can be used in any patient with gout (Table 2). When initiating allopurinol, the safest option is to start all patients on 100 mg/day and increase the dose gradually to attempt to lower the risk of mobilization flares. Achieving full therapeutic benefit, including a reduction in flares, frequently requires doses greater than the commonly used 300 mg/day.¹⁷ The serum urate level should be monitored every 2 weeks during dose escalation until the level is less than 6 mg/dL. Once a stable level is established, the serum urate can be checked once or twice a year to ensure that therapeutic concentrations are maintained.

The rare but potentially fatal hypersensitivity syndrome is a concern with allopurinol. If a rash develops in a patient taking allopurinol, the drug should be discontinued, as rash can be a precursor of severe systemic hypersensitivity.

Renal function must be considered in allopurinol dosing, and treatment should always be initiated at lower doses in patients with renal disease.¹⁸ However, recent reports indicate that allopurinol doses can be gradually and safely increased to an effective level that achieves a serum urate concentration of less than 6 mg/dL even in patients with reduced kidney function.^19,20

Uricosurics

The uricosuric agent probenecid works by increasing the urinary excretion of urate.¹⁰ Probenecid is commonly dosed at 500 mg twice daily, with a maximum daily dose of 2 g, in an attempt to reach the target serum urate level. Probenecid is unlikely to be effective if the patient’s serum creatinine is greater than 2 mg/dL.²¹

When a uricosuric agent is used, a 24-hour urine urate measurement must be taken to identify and exclude urate overproducers (patients with more than 800 to 1,000 mg of uric acid in a good 24-hour collection), as such patients are at risk for uric acid kidney stones. Additionally, aspirin interferes with probenecid’s effect on the renal tubules. The ideal candidate for uricosuric therapy has good kidney function, is not a urate overproducer, and is willing to drink 8 glasses of water a day to minimize the risk of kidney stones (Table 2).

Evidence supporting urate targets and continuous maintenance of urate reductions

If a serum urate level of less than 6 mg/dL is achieved and maintained, gout flares will be reduced and crystals can be depleted from inside the joint.^22–25 Additionally, the size of tophi can be reduced and their recurrence prevented.^26–28 Serum urate levels below 4 mg/dL can result in more rapid dissolution of tophi.²⁶

Reprinted, with permission, from Journal of Rheumatology (Bull PW, Scott JT. J Rheumatol 1989; 16:1246–1248).

Urate-lowering therapy with allopurinol or probenecid is generally a lifelong commitment. Intermittent therapy or cessation of therapy can lead to recurrent attacks.^21,28,29 In a randomized trial examining outcomes of continuous versus intermittent urate-lowering therapy with allopurinol, gout attacks were eliminated after about 2 years of therapy in patients who continuously received allopurinol, whereas they continued to recur beyond 2 years in patients who received allopurinol intermittently (ie, due to the way it was prescribed or nonadherence) (Figure 1).²⁹

Patient commitment and education are essential

No treatment plan will succeed without the commitment of the patient, so discussion to determine the patient’s willingness to commit to lifetime therapy is warranted. A number of surveys have shown that the rate of continued use of allopurinol after it is initially prescribed is less than 50%.¹⁷ If the physician or nurse monitors adherence, however, treatment is more likely to be successful.³⁰

Patients need more education about gout, as education may improve adherence and treatment success. Patient education material is available from the Arthritis Foundation (www.arthritis.org/disease-center.php) and the Gout & Uric Acid Education Society (www.gouteducation.org).

CONCLUSION

A comprehensive treatment strategy is critical to ensure ideal gout therapy. Acute flares should be addressed as rapidly as possible with an anti-inflammatory agent selected on the basis of the patient’s comorbidities and other medications. Most patients require chronic urate-lowering therapy to deplete crystals from joints and prevent flares. Initiation of urate-lowering therapy should be considered early in the disease course, following resolution of the acute attack. Low-dose anti-inflammatory prophylaxis should be initiated when any urate-lowering therapy is started. Regular monitoring of serum urate will ensure effective dosing to achieve a target serum urate level of less than 6 mg/dL. Once urate deposits are depleted, acute flares should cease.