Gout

Introduction

Background

Gout is a common disorder of uric acid metabolism that can lead to deposition of monosodium urate (MSU) crystals in soft tissue, recurrent episodes of debilitating joint inflammation, and, if untreated, joint destruction and renal damage. Gout is definitively diagnosed based on the demonstration of urate crystals in aspirated synovial fluid.

Clinical Image Atlas Click to view clinical images on the features and diagnosis of gout.

Improvements in early diagnosis and the availability of definitive treatment have significantly improved the prognosis of gout, as evidenced by the declining incidence of disabling chronic tophaceous gout. However, tophaceous gout may still develop because of misdiagnosis, poor management, medication intolerances, and/or poor patient compliance.

For additional information on gout, see Medscape’s Gout Resource Center.

Pathophysiology

Although the presence of urate crystals in the soft and synovial tissues is a prerequisite for a gouty attack, the fact that urate crystals can also be found in synovial fluid in the absence of joint inflammation suggests that the mere presence of intrasynovial urate crystals is not sufficient to cause flares of gouty arthritis.

One explanation for this may lie in the observation that clumps or microtophi of highly negatively charged and reactive MSU crystals are normally coated with serum proteins (apolipoprotein [apo] E or apo B) that physically inhibit the binding of MSU crystals to cell receptors.^1,2 A gout attack may be triggered by either a release of uncoated crystals (eg, due to partial dissolution of a microtophus caused by changing serum urate levels) or precipitation of crystals in a supersaturated microenvironment (eg, release of urate due to cellular damage). From either source, naked urate crystals are then believed to interact with intracellular and surface receptors of local dendritic cells and macrophages, serving as a danger signal to activate the innate immune system.³

This interaction may be enhanced by immunoglobulin G (IgG) binding.^4,5 Triggering of these receptors, including Toll-like receptors, NALP3 inflammasomes, and the triggering receptors expressed on myeloid cells (TREMs) by MSU, results in the production of interleukin (IL)–1, which in turn initiates the production of a cascade of pro-inflammatory cytokines, including IL-6, IL-8, neutrophil chemotactic factors, and tumor necrosis factor (TNF)–alpha.⁶ Neutrophil phagocytosis leads to another burst of inflammatory mediator production.

Subsidence of an acute gout attack is due to multiple mechanisms, including the clearance of damaged neutrophils, recoating of urate crystals, and the production of anti-inflammatory cytokines including, IL-1RA, IL-10, and transforming growth factor (TGF)–beta.^7,8,9,5

Frequency

United States

Approximately 1% of the general population have gout.

International

Gout has a worldwide distribution; regional differences may reflect environmental, dietary, and genetic influences.

Mortality/Morbidity

• Gout is associated with considerable morbidity. Acute episodes of gout often lead to incapacitation.
• Untreated chronic tophaceous gout can lead to severe joint destruction.
• MSU deposition in the kidney can result in inflammation and fibrosis, leading to reduced renal function or chronic renal nephropathy.
• Hyperuricemia and gout are associated with an increased overall likelihood of mortality. Whether this is directly attributable to hyperuricemia or gout or to gout-associated diseases (eg, insulin resistance, type 2 diabetes mellitus, abdominal obesity, hypercholesterolemia, hypertension) has been much debated. Although no evidence has shown that gout or hyperuricemia causes any of these disorders, elevated urate levels have been shown to correlate with blood pressure in adolescents,¹⁰ and, among middle-aged men, hyperuricemia with gout was a significant independent risk for death due to cardiovascular disease.¹¹

Race

• Gout is slightly more prevalent in blacks than in whites.

Sex

• The prevalence of gout is 13.6 cases per 1000 men and 6.4 cases per 1000 women.
• This difference is largely a consequence of age at onset because estrogenic hormones have a mild uricosuric effect; therefore, gout is unusual in premenopausal women.

Age

• As a rule, uric acid levels are elevated for 20 years before the onset of gout.
• In men, uric acid levels rise at puberty, and the peak age of onset of gout in men is in the fourth to sixth decade of life. In women, uric acid levels rise at menopause, and peak age of onset in women is in the sixth to eighth decade of life. Gout is unlikely to present in premenopausal women or in men younger than 30 years who do not have renal insufficiency or a genetic abnormality of purine metabolism (eg, hypoxanthine-guanine phosphoribosyltransferase deficiency, phosphoribosylpyrophosphate synthetase superactivity). The higher prevalence of gout in elderly persons may also reflect an increased prevalence of metabolic syndrome, high rates of diuretic treatment for hypertension and congestive heart failure, and the use of low-dose acetylsalicylic acid. Tophi are typically detectable clinically approximately 10 years after the first gout attack.
• Cyclosporin A can cause an accelerated form of gout, even in premenopausal women, that can present after only a few years of hyperuricemia, particularly if the patient is also receiving diuretics.

Clinical

History

• Acute monoarticular arthritis is the initial presentation of gout in 90% of patients.
  • In early gout, only 1 or 2 joints are usually involved. Typically, they are the smaller, lower-extremity joints. Podagra (inflammation of the first metatarsophalangeal joint) is the initial joint manifestation in 50% of cases. Eventually, it is involved in 90% of cases. Podagra is not synonymous with gout. Podagra may be observed in patients with pseudogout, sarcoidosis, gonococcal arthritis, psoriatic arthritis, and reactive arthritis.
    
    

    

    Gout. Acute podagra due to gout in an elderly man.

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    Gout. Acute podagra due to gout in an elderly man.

  • The attacks begin abruptly and reach maximum intensity within 8-12 hours. The joints are red, hot, and exquisitely tender; even a bed sheet on the swollen joint is uncomfortable. Untreated, the first attacks resolve spontaneously in less than 2 weeks.
  • A history of intermittent inflammatory arthritis, in which the joints return to normal between attacks, is typically caused by crystalline disorders and is characteristic of gouty arthritis early in its course.
  • Gout initially presents as polyarticular arthritis in 10% of patients. Elderly women, particularly women with renal insufficiency on a thiazide diuretic, can develop polyarticular arthritis as the first manifestation of gout. These attacks may occur in coexisting Heberden and Bouchard nodes. Such patients may also develop tophi more quickly, occasionally without prior episodes of acute gouty arthritis.^12,13,14
• The pattern of symptoms in untreated gout change over time.
  • The attacks become more polyarticular.
  • Although more joints may become involved, inflammation in a given joint may become less intense.
  • More proximal and upper-extremity joints become involved.
  • Attacks occur more frequently and last longer.
  • Eventually, patients may develop chronic polyarticular arthritis, sometimes nearly symmetrical, that can resemble rheumatoid arthritis. Indeed, chronic polyarticular arthritis that began as an intermittent arthritis should prompt consideration of a crystalline disorder in the differential diagnoses.
• Although gout typically causes joint inflammation, it can also cause inflammation in other synovial-based structures such as bursae and tendons.
• Tophi are collections of urate crystals in the soft tissues. They develop in more than half of patients with untreated gout and may be reported as lumps or nodules. While the classic location of tophi is along the helix of the ear, they can be found in multiple locations, including the fingers, toes, in the olecranon bursae, and along the olecranon, where they can resemble rheumatoid nodules. The finding of a rheumatoid nodule in a patient with a negative rheumatoid factor result or a history of drainage from a nodule should prompt consideration of gout in the differential diagnoses. Tophi are not commonly found during the first gout episode. They tend to develop after 10 years in untreated patients who develop chronic gouty arthritis. Tophi tend to develop earlier in women, particularly those receiving diuretics.^12,13,14
  
  

  

  Gout. Tophaceous deposits in ear.

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  Gout. Tophaceous deposits in ear.

  
  

  

  Gout. Tophaceous deposits on elbow.

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  Gout. Tophaceous deposits on elbow.

  
  

  

  Gout. Chronic tophaceous gout in an untreated patient with end-stage renal disease.

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  Gout. Chronic tophaceous gout in an untreated patient with end-stage renal disease.

• Acute flares of gout can result from situations that lead to increased levels of serum uric acid, such as the consumption of beer or liquor, overconsumption of foods with high purine content, trauma, hemorrhage, dehydration, or the use of medications that elevate levels of uric acid. Acute flares of gout also can result from situations that lead to decreased levels of serum uric acid, such as the use of radiocontrast dye or medications that lower the levels of uric acid, including allopurinol and uricosurics.
• Patients with gout are profoundly more likely to develop renal stones than are healthy individuals (by a factor of 1000); therefore, they may have a history of renal colic. Indeed, renal stones may precede the onset of gout in 40% of affected patients. While 80% of these patients may have stones composed entirely of uric acid, 20% may develop calcium oxalate or calcium phosphate stones with a uric acid core.
• Although patients with gout often have other risk factors for renal disease, including hypertension and diabetes, chronic urate nephropathy can contribute to renal insufficiency. Chronic urate nephropathy in patients with chronic tophaceous gout can result from the deposition of urate crystals in the medullary interstitium and pyramids, resulting in an inflammatory reaction that can lead to fibrotic changes. This process is characterized by hyperuricemia that is disproportional to the degree of renal impairment and is associated with a benign urinary sediment.
• Lead intoxication can damage the renal tubules, leading to impaired proximal tubular function with resultant hyperuricemia and gout.
• Because gout is frequently present in patients with the metabolic syndrome (eg, insulin resistance or diabetes, hypertension, hypertriglyceridemia, and low levels of high-density lipoproteins) and because the presence of these associated disorders can lead to coronary artery disease, these problems should be sought and treated in patients diagnosed with gout.
• Importantly, ask about a history of peptic ulcer disease, renal disease, or other conditions that may complicate the use of the medications used to treat gout.

Physical

• During an acute gout attack, examine all joints to determine if the patient's arthritis is monoarticular or polyarticular.
• Involved joints have all the signs of inflammation: swelling, warmth, erythema, and tenderness.
• The erythema over the joint may resemble cellulitis; the skin may desquamate as the attack subsides.
• The joint capsule becomes quickly swollen, resulting in a loss of range of motion of the involved joint.
• During an acute gout attack, patients may be febrile, particularly if it is an attack of polyarticular gout.
• Look for sites of infection that may have seeded the joint and caused an infectious arthritis that can resemble or coexist with acute gouty arthritis.
• The presence of tophi suggests long-standing hyperuricemia.

Causes

Gout develops in the setting of excessive stores of uric acid in the form of monosodium urate. Uric acid is an end-stage by-product of purine metabolism. Lacking uricase, humans remove uric acid primarily by renal excretion. When excretion is insufficient to maintain serum urate levels below the saturation level of 6.8 mg/dL (with some variability depending on temperature and pH), hyperuricemia may develop, and urate can crystallize and deposit in soft tissues. Ninety percent of patients with gout develop excess urate stores due to an inability to excrete sufficient amounts of normally produced uric acid in the urine (underexcretion). The remaining patients either overconsume purines or produce excessive amounts of uric acid endogenously (overproduction).

• In rare cases, overproduction of uric acid is primary, due to a genetic disorder. These disorders include hypoxanthine-guanine phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome), glucose-6-phosphatase deficiency (von Gierke disease), fructose 1-phosphate aldolase deficiency, and PP-ribose-P synthetase variants.
• Overproduction of uric acid may also occur in disorders that cause high cell turnover with release of purines. These disorders include myeloproliferative and lymphoproliferative disorders, psoriasis, chemotherapy (tissue lysis), hemolytic anemias, pernicious anemia, ineffective erythropoiesis (as in B-12 deficiency), excessive exercise, and obesity.
• Overproduction of uric acid can occur from overconsumption of foods high in purines.
• Common causes of secondary gout due to underexcretion of uric acid include renal insufficiency, lead nephropathy (saturnine gout), starvation or dehydration, hypothyroidism, hyperparathyroidism, drugs (including diuretics and cyclosporine A), and chronic ethanol (especially beer and hard liquor) abuse. These disorders should be identified and corrected, if possible.

Individual gout flares are often triggered by acute increases or decreases in urate levels that may lead to the production, exposure, or shedding of crystals that are not coated with apo B or apo E. This can result from acute alcohol ingestion, acute overindulgence in foods high in purines, rapid weight loss, starvation, trauma, or hemorrhage. Medications that increase uric acid levels via effects on renal tubular transport include diuretics and low-dose aspirin. Gout flares can also result from agents that lower levels of uric acid, including the use of radiocontrast dyes and medications such as allopurinol or uricosurics.

Differential Diagnoses

Calcium Pyrophosphate Deposition Disease	Reactive Arthritis
Cellulitis	Rheumatoid Arthritis
Gonococcal Arthritis	Sarcoidosis
Nephrolithiasis	Septic Arthritis
Nephropathy, Uric Acid
Psoriatic Arthritis

Other Problems to Be Considered

Hypoxanthine-guanine phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome)
Phosphoribosylpyrophosphate synthetase superactivity
Congenital fructose intolerance

Workup

Laboratory Studies

• Synovial fluid: When a patient presents with acute inflammatory monoarticular arthritis, aspiration of the involved joint is critical to rule out an infectious arthritis and to attempt to confirm a diagnosis of gout or pseudogout based on identification of crystals.
  
  

  

  Gout. Fluid obtained from a tophaceous deposit in a patient with gout.

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  Gout. Fluid obtained from a tophaceous deposit in a patient with gout.

  • The critical and essential study is synovial fluid analysis to identify urate crystals. Finding intracellular urate crystals with polarizing light microscopy firmly establishes the diagnosis of gouty arthritis.
  • Urate crystals are shaped like needles or toothpicks with pointed ends.
    
    

    

    Gout. Needles of urate on polarizing microscopy.

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    Gout. Needles of urate on polarizing microscopy.

  • Urate crystals are negatively birefringent, meaning that the crystals are yellow when aligned parallel to the slow ray of the compensator and that they are blue when they are perpendicular.
    
    

    

    Gout. Strongly negative birefringent, needle-shaped crystals diagnostic of gout obtained from an acutely inflamed joint.

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    Gout. Strongly negative birefringent, needle-shaped crystals diagnostic of gout obtained from an acutely inflamed joint.

  • Pseudogout crystals (calcium pyrophosphate) are rod-shaped with blunt ends.
  • Pseudogout crystals are positively birefringent. Pragmatically, this means that their colors are opposite those of gout. Thus, pseudogout crystals are blue when aligned parallel to the slow ray of the compensator and yellow when they are perpendicular.
  • Crystals need to be distinguished from birefringent cartilaginous or other debris. Debris may have fuzzy borders and may be curved, whereas crystals have sharp borders and are straight.
  • Corticosteroids injected into joints have a crystalline structure that can mimic monosodium urate crystals. They can be either positively or negatively birefringent.
  • The sensitivity of a synovial fluid analysis for crystals is 84%, with a specificity of 100%. If gout remains a clinical consideration after negative analysis findings, the procedure can be repeated in another joint or with a subsequent flare. Crystals may be absent very early in a flare.
  • While the sensitivity is inferior, urate crystals can be identified from synovial fluid aspirated from previously inflamed joints that are not currently inflamed. Such crystals are generally extracellular.
  • Minute quantities of fluid in the shaft or hub of the needle are sufficient for synovial fluid analysis.
  • Once a diagnosis of gout is established based on confirmation of crystals, joints do not need repeat aspiration with subsequent flares unless infection is suggested or the flare does not respond appropriately to therapy for acute gout.
  • In patients with acute monoarticular arthritis, send synovial fluid for Gram stain and culture and sensitivity. The culture also provides sensitivities for antibiotic management.
  • Synovial fluid should also be sent for cell count.
  • During acute attacks, the synovial fluid is inflammatory, with a WBC count greater than 2000/µL (class II fluid) and possibly greater than 50,000/µL, with a predominance of polymorphonuclear neutrophils.
  • Synovial fluid glucose levels are usually normal, whereas they may be depressed in septic arthritis and occasionally in rheumatoid arthritis. Measurement of synovial fluid protein has no clinical value.
  • Crystalline arthritis and infectious arthritis can coexist. Indeed, infectious arthritis is more common in previously damaged joints, which may occur in patients with chronic gouty arthritis.
• Serum uric acid
  • This is the most misused test in the diagnosis of gout. The presence of hyperuricemia in the absence of symptoms is not diagnostic of gout. In addition, as many as 10% of patients with symptoms due to gout may have normal serum uric acid levels at the time of their attack. Thus, the correct diagnosis of gout can be missed if the joint is not aspirated. Remember that situations that decrease uric acid levels can trigger attacks of gout. In such cases, the patient's prior medical records may reveal prior elevations of uric acid.
  • Five to eight percent of the population has elevated serum uric acid levels (>7 mg/dL), but only 5-20% of patients with hyperuricemia develop gout. Thus, an elevated serum uric acid level does not indicate or predict gout. As noted above, gout is diagnosed based on the discovery of urate crystals in the synovial fluid or soft tissues. More importantly, some patients with infectious arthritis present with a hot swollen joint and an elevated serum uric acid level and are at risk of being mismanaged if their synovial fluid is not aspirated to rule out septic arthritis.
  • Asymptomatic hyperuricemia should generally not be treated. However, patients with levels higher than 11 mg/dL and overexcretion of uric acid are at risk for renal stones and renal impairment; therefore, renal function should be monitored in these individuals.¹⁵
  • The level of serum uric acid correlates with risk for developing gout. The 5-year risk for developing gout is approximately 0.6% if the level is less than 7.9 mg/dL, 1% if 8-8.9 mg/dL, and 22% if higher than 9 mg/dL.
• Uric acid in 24-hour urine sample
  • A 24-hour urinary uric acid evaluation is generally performed if uricosuric therapy is being considered.
  • If patients excrete more than 800 mg of uric acid in 24 hours on a regular diet, they are overexcretors and thus overproducers of uric acid. These patients (approximately 10% of patients with gout) require allopurinol instead of probenecid to reduce uric acid levels.
  • Patients who excrete more than 1100 mg in 24 hours should undergo close renal function monitoring because of the risk of stones and urate nephropathy.
  • In patients in whom probenecid is contraindicated (eg, those with a history of renal stones or renal insufficiency), a 24-hour urine test of uric acid excretion does not need to be performed because the patient clearly will need allopurinol.
• Blood chemistry
  • Obtaining an accurate measure of the patient's renal function before deciding on therapy for gout is important, since the serum creatinine evaluation alone can underestimate renal dysfunction in elderly patients or in patients with low muscle mass.
  • Patients with gout are at an increased risk of developing diabetes mellitus.
  • Abnormal liver function tests need to be considered when therapy is selected.
• CBC count: The WBC count may be elevated in patients during the acute gouty attack, particularly if it is polyarticular.
• Lipids: Hypertriglyceridemia and low high-density lipoproteins are associated with gout.
• Urinalysis: Patients with gout are at an increased risk of renal stones; therefore, these patients may have a history of hematuria.

Imaging Studies

• Radiography
  • Plain radiographs may show findings consistent with gout, but these findings are not diagnostic. The most common radiographic findings early in the disease include soft-tissue swelling or an absence of abnormalities.
  • Haziness suggestive of tophi can be seen in late gout, and tophi may calcify.
  • Erosions that are not typical of rheumatoid arthritis may suggest gout.
    • Erosions with maintenance of the joint space
    • Erosions without periarticular osteopenia
    • Erosions outside the joint capsule
    • Erosions with overhanging edges
      
      

      

      Gout. Radiograph of erosions with overhanging edges.

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      Gout. Radiograph of erosions with overhanging edges.

    • Erosions with sclerotic borders, sometimes called cookie-cutter or punched-out borders
    • Erosions that are distributed asymmetrically among the joints, with strong predilection for distal joints, especially in the lower extremities
      
      

      

      Gout. Plain radiograph showing typical changes of gout in the first metatarsophalangeal joint and fourth interphalangeal joint.

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      Gout. Plain radiograph showing typical changes of gout in the first metatarsophalangeal joint and fourth interphalangeal joint.

      
      
      

      

      Gout. Plain radiograph showing chronic tophaceous gouty arthritis in the hands.

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      Gout. Plain radiograph showing chronic tophaceous gouty arthritis in the hands.

Procedures

Perform arthrocentesis to rule out an infectious arthritis and to establish a crystal-proven diagnosis of gout. Tophi also may be aspirated for crystal analysis under polarizing microscopy.

Histologic Findings

Tophi have been found in all tissues except the brain. However, monosodium urate dissolves in formalin; therefore, only the ghosts of urate crystals may be seen if formalin is used. Alcohol-fixed tissue is best for identification of urate crystals.

Treatment

Medical Care

Gout is managed in 3 stages: (1) treating the acute attack, (2) providing prophylaxis to prevent acute flares, and (3) lowering excess stores of urate to prevent flares of gouty arthritis and to prevent tissue deposition of urate crystals.

As mentioned above, asymptomatic hyperuricemia should generally not be treated. However, patients with levels higher than 11 mg/dL who overexcrete uric acid are at risk for renal stones and renal impairment; therefore, renal function should be monitored in these individuals.¹⁵

Acute gout

Options for treatment of acute gout include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and colchicine (a classic treatment that is now rarely indicated). The choice is based primarily on any concomitant health problems (eg, renal insufficiency, peptic ulcer disease).

• Nonsteroidal anti-inflammatory drugs
  • NSAIDs are the drugs of choice in most patients with gout who do not have underlying health problems.
  • Although indomethacin is the traditional NSAID of choice for acute gout (unless the patient is elderly, because of the potential for adverse CNS effects in this age group), most NSAIDs can be used. Select an agent with a quick onset of action, but do not use aspirin because it can alter uric acid levels and potentially prolong and intensify an acute attack. Cyclooxygenase-2 (COX-2) inhibitors have been used with success.
  • Start with the highest dose for 2-3 days and taper down over approximately 2 weeks. Gout symptoms should be absent for at least 2 days before the NSAID is discontinued.
  • Avoid NSAIDs in patients who have a history of peptic ulcer disease or GI bleeding, patients with renal insufficiency, patients with abnormal hepatic function, patients taking warfarin (selective COX-2 inhibitors can be used), and patients in the intensive care unit who are predisposed to gastritis. Use NSAIDs cautiously in patients with diabetes and those who are receiving concomitant angiotensin-converting enzyme (ACE) inhibitors.
• Corticosteroids
  • Corticosteroids can be given to patients with gout who cannot use NSAIDs or colchicine. Some rheumatologists recommend corticosteroids over NSAIDs as the preferred choice for treatment of acute gout. Steroids can be given orally, intravenously, intramuscularly, intra-articularly, or indirectly via adrenocorticotropic hormone (ACTH).
  • Prednisone can be given at a dose of approximately 40 mg for 1-3 days and then tapered over approximately 2 weeks. Tapering more rapidly can result in a rebound flare.
  • Using parenteral corticosteroids confers no advantage unless the patient cannot take oral medications.
  • Intra-articular corticosteroids are particularly useful in patients with a monoarticular flare to help reduce the systemic effects of oral steroids. Ensuring that the joint is not infected prior to injecting intra-articular corticosteroids is particularly important.
  • ACTH at 40 IU IM can be given to induce corticosteroid production by the patient's own adrenal glands. Such a regimen does not depend on the patient to taper prednisone properly.
• Colchicine
  • Colchicine in acute gout
    • Although colchicine was once the treatment of choice for acute gout, it is now a second-line approach because of its narrow therapeutic window and risk of toxicity.¹⁶ When used in classic hourly dosing regimens in acute gout, colchicine causes adverse GI effects, particularly diarrhea and vomiting, in 80% of patients.
    • Dosing recommendations for colchicine in acute gout therapy have been modified in recent years because of an increased awareness of its toxicities. The most recent recommendations have been trending toward lowered daily and cumulative doses. A task force of The EULAR Standing Committee for International Clinical Studies has developed evidence-based guidelines that recommend colchicine dosing in acute gout of 0.5 mg tid (0.6 mg tid in the United States).¹⁷ An alternative regimen suggested by the New Zealand Medicines and Medical Devices Safety Authority is as follows: 1 mg loading dose followed by 0.5 (0.6) mg every 6 hours, up to a maximum of 2.5 mg/24 hours and 6 mg over 4 days.¹⁶
    • Patients with gout may be able to abort an attack by taking a single colchicine tablet at the first twinge of an attack.
    • Colchicine should not be used if the glomerular filtration rate (GFR) is less than 10 mL/min, and the dose should be decreased by at least half if the GFR is less than 50 mL/min.
    • Colchicine should also be avoided in patients with hepatic dysfunction, biliary obstruction, or an inability to tolerate diarrhea.
    • A clinical response to colchicine is not pathognomonic for gout and may occur in patients with pseudogout, sarcoid arthropathy, psoriatic arthritis, or calcific tendonitis.
    • In February 2008, the US Food and Drug Administration (FDA) ruled that intravenous colchicine can no longer be produced or shipped in the United States because of its toxicities. Because of this, intravenous colchicine is no longer advocated for the treatment of acute gout in the United States.¹⁸
  • Colchicine as a prophylaxis against recurrence of acute flares
    • Lowering uric acid with either allopurinol or probenecid can precipitate attacks of gout. When used prophylactically, colchicine can reduce such flares by 85%.¹⁹
    • The standard dose for prophylaxis is colchicine 0.6 mg bid. In patients with renal insufficiency, this dose may need to be decreased to daily or every-other-day administration.
    • Compared with the 80% risk of adverse GI effects in patients using classic hourly colchicine for the treatment of acute gout, the prophylactic dose of colchicine induces adverse GI effects in only 4% of patients.
    • Long-term use of colchicine can lead to a muscle weakness associated with elevated levels of creatine kinase due to a drug-induced neuromyopathy, particularly in patients with renal insufficiency.²⁰
    • In patients who cannot take colchicine, NSAIDs, such as indomethacin at 25 mg bid, can be used for prophylaxis. If NSAIDs are contraindicated, low doses of prednisone can be considered.
    • Prophylaxis with colchicine can be started during an acute attack.

Chronic gout

Long-term management of gout is focused on lowering uric acid levels. The goal of therapy is to lower serum uric acid levels to approximately 6 mg/dL or less.

In many cases, patients who have a first attack of gout should undergo therapy with agents that lower uric acid, given the high risk for further inflammatory attacks and the potential for destructive tophaceous deposition in the bone, synovium, and kidney, even without episodes of acute inflammation. However, some rheumatologists advocate waiting for the second attack to initiate therapy to lower uric acid levels because not all patients experience a second attack and because some patients may need to be convinced they need life-long therapy. The risk of a second attack of gout after the first attack is 62% after 1 year, 78% after 2 years, and 93% after 10 years. The decision to begin therapy depends partly on the baseline serum uric acid levels (>9 mg/dL denotes a higher risk for recurrent gouty arthritis and tophi).

Monotherapy with colchicine may help prevent flares of inflammatory arthritis but does not prevent the accumulation of uric acid in the joints, which can lead to further joint destruction. In all cases, the risks and benefits need to be judged based on the individual patient. For instance, in an elderly patient with multiple underlying medical problems and renal insufficiency, the risks of therapy to lower uric acid levels may outweigh the benefits.

Agents that lower uric acid levels should not be initiated during an acute attack. This may lead to a more intense and prolonged attack. Typically, they should be started a few weeks after the attack has resolved and with the protection of prophylactic colchicine to prevent another attack. If the patient develops a gout flare after beginning therapy with a uric acid–lowering agent, the agent should not be discontinued because this will only cause another flux in the uric acid level, which may prolong and intensify the attack.

• Probenecid
  • Some rheumatologists prefer probenecid whenever possible because it has fewer significant adverse effects than allopurinol. Probenecid can be used in most middle-aged patients with gout who are otherwise healthy.
  • Indications for the use of allopurinol instead of probenecid include renal insufficiency (GFR <50>
  • Drug interactions may occur with probenecid (see Medication).
  • Patients who use probenecid need to drink 2 L of fluid daily at the inception of therapy in order to reduce their urinary concentration and thereby reduce the risk of renal stones.
• Allopurinol
  • Allopurinol blocks xanthine oxidase and thus reduces the generation of uric acid. Therefore, it should be used in patients who overproduce uric acid and in patients at risk of tumor lysis syndrome to prevent renal toxicity during therapy for malignancies. It is the most effective urate-lowering agent. However, alcohol can interfere with the effectiveness of allopurinol.
  • Approximately 3-10% of patients taking allopurinol develop dyspepsia, headache, diarrhea, and/or pruritic maculopapular rash. Less frequently, patients taking allopurinol can develop allopurinol hypersensitivity, which carries a mortality rate of 20-30%. Features of allopurinol hypersensitivity include fever, toxic epidermal necrolysis, bone marrow suppression, eosinophilia, leukocytosis, renal failure, hepatic failure, and vasculitis. Corticosteroids are often used to treat allopurinol hypersensitivity.
  • Allopurinol hypersensitivity is more likely to occur in patients with renal insufficiency, patients who are taking a diuretic, and patients begun on 300 mg of allopurinol.²¹ Although allopurinol hypersensitivity is more common (although still rare) in patients with renal insufficiency, this effect does not appear to be dose-related.²² Thus, a slow and careful titration of allopurinol dosing sufficient to achieve uric acid levels of less than 6 mg/dL is also recommended in these patients.²³
  • Allopurinol should be discontinued in patients who develop a rash. In patients with a history of drug eruptions due to allopurinol, both oral²⁴ and intravenous²⁵ desensitization regimens can be considered.
  • In most patients, start at 100 mg per day (50 mg in patients with renal insufficiency) and adjust the dose monthly according to the uric acid level until the goal of a uric acid level of 6 mg/dL or less is achieved.
  • Beware of drug interactions. For example, allopurinol prolongs the half-life of azathioprine and 6-mercaptopurine. It enhances the bone marrow toxicity of cyclophosphamide. Patients taking concomitant ampicillin are at an increased risk of rash.
  • Once the target uric acid level is achieved and maintained for 6 months, discontinue colchicine prophylaxis.
  • Avoiding the use of medications that elevate uric acid in patients with gout is prudent. Thus, other agents are preferable to a thiazide diuretic to treat hypertension. However, if such a medication is needed, it can be used with appropriate adjustments of allopurinol or probenecid.
  • Allopurinol can be used in combination with probenecid. However, note that allopurinol increases the half-life of probenecid, whereas probenecid increases the excretion of allopurinol.

Other therapeutic options

• Nonrecombinant urate-oxidase (uricase) is used in Europe to prevent severe hyperuricemia induced by chemotherapy in patients with malignancies, as well as in selected patients with treatment-refractory gout. Recently, the FDA approved recombinant Aspergillus flavus uricase for the prevention of tumor lysis syndrome. However, it is highly immunogenic and may cause anaphylaxis.²⁶ A polyethylene-glycol linked uricase is currently being evaluated. In theory, short-term use of such agents in patients with severe tophaceous could debulk the total-body urate load, allowing for maintenance with probenecid or allopurinol.
• Patients with allopurinol hypersensitivity can often tolerate oxypurinol, which is a metabolite of allopurinol.²⁷ It is available on a "compassionate use" basis. Cross-reactivity with allopurinol can occur.
• Benzbromarone is an effective uricosuric agent that may eventually become available. However, it can cause fulminant hepatotoxicity.
• Febuxostat, a nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol in patients with gout. Febuxostat is administered orally and is metabolized mainly in the liver. In contrast, allopurinol and its metabolites are excreted primarily by the kidney. Therefore, febuxostat can be administered in patents with renal insufficiency, with no dosage adjustment. Its efficacy and side-effect profile otherwise appears similar to that of allopurinol.²⁸
• The angiotensin receptor blocker losartan and the triglyceride-lowering agent micronized fenofibrate have moderately potent uricosuric effects. They should therefore be considered in patients with gout who also require treatment for hypertension and hypertriglyceridemia.²⁶
• Vitamin C, with its uricosuric effect, may reduce the serum concentration of uric acid.²⁹
• In an open-label pilot study of 10 patients with refractory acute gout treated with the IL-1 antagonist anakinra, pain was substantially reduced in all patients within two days, without side effects. Clinical signs of inflammation had disappeared in 9 of 10 patients by the third day of treatment.³⁰

Surgical Care

• In patients with gout that is diagnosed and treated early, orthopedic surgery is usually unnecessary. In patients with untreated gout or gout that is treated late in the disease course, orthopedic repair may be necessary.
• Tophi should not be surgically removed unless they are in a critical location or drain chronically.
• In patients undergoing arthroscopy, the presence of white lesions, sometimes on an erythematous base, should prompt consideration of gout.

Consultations

Rheumatologists should be involved in the care of patients with gout. They can establish the diagnosis with arthrocentesis and synovial fluid analysis for crystals. They also are skilled in the management of this disorder.

Diet

• Diet modifications can improve the serum uric acid levels by only 1 mg/dL and are rarely able to lower uric acid levels sufficiently to prevent further attacks and accumulation of urate.
• Patients with gout should avoid beer and hard liquor because they elevate levels of uric acid and therefore can precipitate attacks of gout. Indeed, heavy drinkers are much more likely to have recurrent gout attacks, even with allopurinol therapy. Moderate wine intake is not associated with an increased gout flares.³¹
• Particularly because of the association of gout with atherosclerosis, the diagnosis of gout may be a good time to advise a low-cholesterol, low-fat diet if otherwise appropriate for the patient. While such a diet may help uric acid levels, such advice should be given primarily to help prevent atherosclerosis.
• Weight reduction in patients who are obese can improve hyperuricemia.

Activity

Patients with gout should avoid using the inflamed joint during an acute attack. Otherwise, they should be active.

Medication

Acute inflammation due to gout can be treated with NSAIDs, corticosteroids, or, rarely, colchicine. NSAIDs are generally the drugs of choice unless the patient has a risk factor that contraindicates these agents. Ultimately, gout is treated by decreasing tissue stores of uric acid with allopurinol or probenecid. Because agents that lower uric acid can precipitate attacks of gout, low-dose colchicine is used as prophylaxis when such therapy is initiated.

Nonsteroidal anti-inflammatory drugs

These agents as a class are the drugs of choice to treat acute inflammation of gout in patients who can safely take these medications.

Indomethacin (Indocin)

The traditional NSAID used to treat acute inflammation in gout, although other NSAIDs can be used effectively. These agents block cyclooxygenase and, thereby, the generation of prostaglandins. Use maximum level of NSAID and taper over approximately 2 weeks, depending on patient's response.

• Dosing
• Interactions
• Contraindications
• Precautions

Adult

50 mg PO tid or qid for 1-3 d, depending on response, and begin tapering

Pediatric

Not established

• Dosing
• Interactions
• Contraindications
• Precautions

Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase the INR when taking anticoagulants (patients on anticoagulants should consider alternative therapy); phenytoin levels may be increased when administered concurrently

• Dosing
• Interactions
• Contraindications
• Precautions

Documented hypersensitivity, patient on anticoagulation, GI bleeding, renal insufficiency, thrombocytopenia

• Dosing
• Interactions
• Contraindications
• Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis may occur; increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion; GI toxicity may include nausea, dyspepsia, abdominal pain, diarrhea, and bleeding; reversible leukopenia may occur (discontinue if persistent leukopenia, granulocytopenia, or thrombocytopenia occurs)

Anti-inflammatory agents

Colchicine is now considered a second-line agent in the treatment of acute gout flares because of its narrow therapeutic window. More often, it is used at a lower dose as a prophylactic agent to prevent flares of gout when adding agents that lower uric acid.

Colchicine (Colcrys)

Inhibits microtubules and thereby may inhibit phagocytosis, neutrophil mobility, and chemotaxis. Also may inhibit generation of prostaglandins.

Corticosteroids

These agents are potent and effective anti-inflammatory drugs that can be used to treat acute gout in patients who cannot tolerate NSAIDs or colchicine. Steroids can be given PO, IM, IV, intra-articularly, or indirectly via ACTH. The short-burst therapy of corticosteroids necessary to treat an acute flare of gout is generally well tolerated and not associated with the chronic adverse effects associated with long-term steroid use. In many patients, a short course of steroids is a safer option than NSAIDs and colchicine. In patients with only 1 or 2 involved joints, intra-articular corticosteroids are a safe and effective treatment option.

Prednisone (Deltasone, Orasone, Meticorten)

Can be given PO to abort an attack of gout. No intrinsic advantage to treating with IV corticosteroids exists unless the patient cannot take medications PO. The advantage of intra-articular steroids is that they reduce the systemic effects of PO steroids, but care must be taken to make sure the joint is not infected. ACTH also can be used to induce the patient's own adrenal gland to produce corticosteroids.
Steroid dose packs that clearly label the dose to be taken each day can be convenient for some patients.

Uricosuric agents

Uricosuric agents lower uric acid levels by increasing net renal excretion of uric acid. They are better tolerated than allopurinol but are less effective and cannot be used in all circumstances. These agents increase the risk of renal stones. These agents should not be started during an attack of acute gouty arthritis. The goal of therapy is to lower serum uric acid to approximately 5-6 mg/dL without causing renal stones.

Xanthine oxidase inhibitors

These agents prevent the generation of uric acid and thereby reduce the tissue stores of uric acid. Allopurinol is more likely to be effective than uricosuric agents but carries an increased risk for significant adverse effects. Allopurinol should not be started during an attack of acute gouty arthritis. The goal of therapy is to lower the serum uric acid level to approximately 5-6 mg/dL.

Source : Medscape