AUTHOR AND EDITOR INFORMATION

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• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
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INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Background

Gout is a common disorder of uric acid metabolism that can lead to recurrent episodes of joint inflammation, tissue deposition of uric acid crystals, and joint destruction if left untreated. Unlike many other rheumatic diseases, gout is very treatable. A definitive diagnosis can be made using joint aspiration and synovial fluid analysis. Early diagnosis and treatment have made a significant impact in this disorder, as evidenced by the declining incidence of chronic tophaceous gout. However, tophaceous gout may occur due to misdiagnosis, poor management, and poor patient compliance.

Pathophysiology

Gout is caused by excess stores of uric acid that accumulate in tissues, including the synovium. Lowering serum uric acid levels can prevent attacks of gouty arthritis. However, urate crystals also can be found in synovial fluid in the absence of joint inflammation. Thus, the mere presence of intrasynovial urate crystals is not sufficient to cause flares of gouty arthritis.

Because urate crystals can be coated with apolipoprotein (apo) E or apo B, a reasonable hypothesis is that this protein coating prevents the crystals from triggering an inflammatory response. Therefore, situations that lead to exposure of bare areas of the crystals may trigger an inflammatory response. Clinically, gout flares can be triggered by fluxes in uric acid levels or by microtrauma, each of which can lead to shedding of uncoated crystals. When bare areas of the urate crystals are exposed, they can bind immunoglobulin G (IgG). Such binding stimulates neutrophils to engulf and phagocytose the crystals. Once this occurs, there is a brisk influx of neutrophils associated with elevated levels of interleukin-1, interleukin-6, interleukin-8, tumor necrosis factor-alpha, prostaglandin E2, leukotriene B4, kinins, C5a, and other inflammatory mediators. It is also conceivable is that recoating of uric acid crystals by apo E or apo B could lead to the spontaneous resolution of attacks.

Frequency

United States

Gout is present in approximately 1% of the general population.

International

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

Mortality/Morbidity

• Gout is associated with considerable morbidity. During acute episodes, patients often are incapacitated.
• Untreated chronic tophaceous gout can develop and lead to severe joint destruction.
• Hyperuricemia is associated with increased all-cause mortality. This is not due to gout, per se, but to diseases associated with gout, such as insulin resistance, type 2 diabetes mellitus, abdominal obesity, hypercholesterolemia, and hypertension.

Race

• Blacks have a slightly higher prevalence compared to whites.

Sex

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

Age

• As a general rule, uric acid levels are elevated for 20 years before the onset of gout.
• In men, uric acid levels rise at puberty, and peak age of onset of gout is in the fourth to sixth decades. In women, uric acid levels rise at menopause, and peak age of onset is in the sixth to eighth decades. Gout is unlikely to present in premenopausal women or in men younger than 30 years unless renal insufficiency or a genetic abnormality of purine metabolism is present, such as hypoxanthine-guanine phosphoribosyltransferase deficiency or phosphoribosylpyrophosphate synthetase superactivity. The higher prevalence of gout in elderly persons may also reflect an increased prevalence of the metabolic syndrome, high rates of diuretic treatment for hypertension and congestive heart failure, and the use of low-dose acetylsalicylic acid. Typically, tophi may be clinically detected approximately 10 years after the first attack of gout.
• 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 also is treated with diuretics.

CLINICAL

Section 3 of 11  

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History

• Acute monoarticular arthritis is the initial presentation of gout in 90% of patients.
• • In early gout, usually only 1 or 2 joints are involved. Typically, they are the smaller, lower-extremity joints.
  • Podagra (inflammation of the first metatarsophalangeal joint) is the initial joint manifestation involved in 50% of cases. Eventually, it is involved in 90% of cases.
  • Podagra is not synonymous with gout. Podagra can be observed in patients with pseudogout, sarcoidosis, gonococcal arthritis, psoriatic arthritis, and reactive arthritis.
  • The attacks begin abruptly and reach maximum intensity in 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. Intermittent inflammatory arthritis, in which the joints return to normal between attacks, typically is caused by crystalline disorders and is true of gouty arthritis early in its course.
  • Gout can initially present as a polyarticular arthritis in 10% of patients. Elderly women, particularly women with renal insufficiency and taking a thiazide diuretic, often develop polyarticular arthritis as their first manifestation of gout. These attacks may occur in coexisting Heberden and Bouchard nodes. Such patients also may develop tophi more quickly, occasionally without prior episodes of acute gouty arthritis.
• Untreated, the clinical characteristics of 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 a chronic polyarticular arthritis, sometimes nearly symmetrical, that can resemble rheumatoid arthritis. Indeed, if a patient presents with a chronic polyarticular arthritis that began as an intermittent arthritis, a crystalline disorder should be considered in the differential diagnosis.
• While gout typically causes inflammation in a joint, it also can cause inflammation in other synovial-based structures such as bursas and tendons.
• Tophi are collections of uric acid crystals in the soft tissues. They occur in more than half of untreated patients. While the classic location 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 should prompt the clinician to consider gout in the differential diagnosis. Finding tophi during the first episode of gout is unusual; they tend to develop after 10 years in untreated patients who develop chronic gouty arthritis.
• Acute flares of gout can occur in situations that lead to increased levels of serum uric acid, such as the use of alcohol, overindulgence of certain foods, trauma, hemorrhage, or the use of medications that elevate levels of uric acid. Situations that lead to the rapid depletion of adenosine triphosphate (ATP) can result in the accumulation of adenosine 5'-diphosphate, adenosine monophosphate (AMP), and, subsequently uric acid. Alcohol, for example, accelerates the conversion of ATP to AMP. Alcohol also increases lactate relative to pyruvate and thereby reduces the excretion of uric acid. Beer contains guanosine and thereby increases the purine load.
• Acute flares of gout also can occur in 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.
• Patients with gout have a 1000-fold increased incidence of renal stones and therefore may have a history of renal colic. Indeed, renal stones may precede the onset of gout in 40% of 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. Patients with gout also are prone to develop urate nephropathy, in which uric acid crystals are deposited in the medullary interstitium and pyramids. While patients with gout have a higher incidence of renal impairment, whether hyperuricemia is an independent risk factor for this remains unclear because such patients have a higher incidence of hypertension, diabetes, and other risk factors for renal insufficiency.
• Patients with gout often are clustered with the insulin resistance syndrome known as metabolic syndrome or syndrome X: diabetes, hypertension, hypertriglyceridemia, and low high-density lipoproteins. No evidence indicates that gout or hyperuricemia cause any of these other disorders. Because the presence of these associated disorders can lead to coronary artery disease, the incidence of which also is increased in patients with gout, these problems should be sought and treated in patients diagnosed with gout. However, no evidence indicates that gout is an independent risk factor for atherosclerosis.
• Importantly, ask about a history of peptic ulcer disease, renal disease, or other conditions that may complicate the use of the medications to treat gout.

Physical

• During an acute attack, examine all joints to determine if the patient's arthritis is monoarticular or polyarticular.
• Involved joints show all the signs of inflammation: swelling, warmth, erythema, and tenderness.
• The erythema over the joint can resemble cellulitis, and 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 can have a fever, particularly if it is an attack of polyarticular gout.
• Look for sites of infection that could have potentially 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 can develop when excessive stores of uric acid are present. Uric acid is a byproduct of purine metabolism. Lacking uricase, humans remove uric acid primarily by renal excretion. Of patients with primary gout, 90% develop excess stores of uric acid because they are unable to excrete sufficient amounts of uric acid in their urine (underexcretion). The remaining patients produce excessive amounts of uric acid (overproduction). When uric acid levels exceed 6.8 mg/dL, with some variability depending on temperature and pH, uric acid can crystallize.

Individual attacks of gout often are triggered by acute fluxes in uric acid levels that may lead to the exposure or shedding of crystals that are not coated with apo B or apo E. This can result from alcohol ingestion, overindulgence in certain foods, starvation, trauma, hemorrhage, or medications such as diuretics. It also can result from situations that lower levels of uric acid, including the use of radiocontrast dyes and medications such as allopurinol.

• Rarely, overproduction of uric acid is due to genetic disorders. These include hypoxanthine-guanine phosphoribosyl transferase deficiency (Lesch-Nyhan syndrome), glucose-6-phosphatase deficiency (von Gierke disease), fructose1-phosphate aldolase deficiency, and PP-ribose-P synthetase variants.
• Overproduction of uric acid also can occur secondary to disorders causing high cell turnover. These include myeloproliferative and lymphoproliferative disorders, psoriasis, chemotherapy (tissue lysis), hemolytic anemias, excessive exercise, and obesity.
• More common causes of secondary gout include renal insufficiency, lead nephropathy (saturnine gout), starvation or dehydration, hypothyroidism, hyperparathyroidism, drugs (including diuretics and cyclosporine A), and ethanol abuse. These disorders should be identified and corrected if possible.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

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

WORKUP

Section 5 of 11  

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Lab 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 by crystal identification.
• • The critical and essential study is synovial fluid analysis to identify urate crystals. Finding intracellular urate crystals by polarizing light microscopy firmly establishes a positive diagnosis of gouty arthritis.
  • Urate crystals are shaped like needles or toothpicks with pointed ends.
  • Urate crystals are negatively birefringent. Pragmatically, this means that the crystals are yellow when aligned parallel to the slow ray of the compensator and that they are blue when they are perpendicular.
  • Pseudogout crystals (calcium pyrophosphate) are rod-shaped with blunt ends.
  • Pseudogout crystals are positively birefringent. Pragmatically, this means that the colors are the opposite 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 used to inject joints have a crystalline structure that can be either positively or negatively birefringent. Therefore, interpreting polarized microscopy from a joint that was recently injected with corticosteroids is difficult.
  • The sensitivity of a synovial fluid analysis for crystals is 84%, with a specificity of 100%. If gout remains a clinical consideration after a negative analysis, the procedure can be repeated in another joint or with a subsequent flare.
  • While the sensitivity is less, urate crystals can be identified from synovial fluid aspirated from previously inflamed joints that are not currently inflamed. These generally are extracellular.
  • Minute quantities of fluid in the shaft or hub of the needle are sufficient for synovial fluid analysis.
  • Once a crystal diagnosis of gout is established, 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.
  • For 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 also should be sent for cell count.
  • During acute attacks, the synovial fluid is inflammatory, with a WBC count greater than 2000/microliter (class II fluid) and possibly greater than 50,000/microliter with a predominance of polymorphonuclear neutrophils.
  • Synovial fluid glucose usually is normal, whereas in septic arthritis and occasionally rheumatoid arthritis, it may be depressed. 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 chronic gouty arthritis.
• Serum uric acid
• • This is the most misused test in the diagnosis of gout.
  • 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, the presence of an elevated level of serum uric acid does not mean the patient has gout or will develop gout. Gout is diagnosed by finding urate crystals in the synovial fluid or soft tissues. More importantly, a number of patients with infectious arthritis present with a hot swollen joint and an elevated serum uric acid level. These patients will be mismanaged if their synovial fluid is not aspirated to determine that they have septic arthritis.
  • Asymptomatic hyperuricemia should 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.
  • The risk for developing gout increases with the level of serum uric acid. 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.
  • As many as 10% of patients with gout 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 because their uric acid level is normal. Remember that situations that lower uric acid levels can trigger attacks of gout. However, the patient's prior medical records should reveal prior elevations of uric acid.
  • Elevated levels of serum uric acid can be observed in other disorders such as myeloproliferative disorders, polycythemia vera, psoriasis, sarcoidosis, hyperparathyroidism, hypothyroidism, pernicious anemia, and sickle cell anemia.
• Uric acid in 24-hour urine sample
• • 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.
  • Patients who excrete more than 1100 mg in 24 hours should have renal function monitored closely because of the risk of stones and urate nephropathy.
  • Patients who are overproducers of uric acid, only 10% of patients with gout, require allopurinol instead of probenecid to lower their uric acid.
  • If the patient already has a contraindication for using probenecid, such as a history of renal stones or renal insufficiency, then 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 estimate of the patient's renal function before deciding on therapy for gout is important. Remember that the serum creatinine alone can overestimate renal function in elderly patients or in patients with low muscle mass.
  • Patients with gout have a higher incidence of diabetes mellitus.
  • Abnormal liver function tests need to be considered when selecting therapy.
• CBC count: WBC count can 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 have a high incidence of renal stones; therefore, patients may have or may have had hematuria.

Imaging Studies

• Plain radiographs may show findings consistent with gout, but these findings are not diagnostic. The most common radiographic finding early in the disease is soft-tissue swelling or a normal radiograph.
• 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
  • 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

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, uric acid dissolves in formalin; therefore, only the ghosts of uric acid crystals may be seen if formalin is used. Alcohol-fixed tissue is best for identification of uric acid crystals.

TREATMENT

Section 6 of 11  

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Medical Care

There are 3 stages in the management of gout: (1) treating the acute attack, (2) providing prophylaxis to prevent acute flares, and (3) lowering excess stores of uric acid to prevent flares of gouty arthritis and to prevent tissue deposition of uric crystals.

• Management of acute gout: Options for treatment of acute gout include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or colchicine (a classic treatment but now rarely indicated). The choice is based primarily on the patient's other health problems, such as renal insufficiency and peptic ulcer disease.
• • Nonsteroidal anti-inflammatory drugs
  • • NSAIDs are the drugs of choice in most patients without underlying health problems.
    • Indomethacin is the traditional choice unless the patient is elderly, because of the potential for adverse CNS effects in this age group. However, 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. Patients should be asymptomatic for at least 2 days before discontinuing the NSAID.
    • 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 coumadin (selective COX-2 inhibitors can be used), and patients in the intensive care unit who are predisposed to gastritis.
  • Corticosteroids
  • • Corticosteroids can be given to those patients 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 effect 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 is the classic medication for gout but is not the preferred medication for the treatment of acute gout. It is most effective during the first 12-24 hours of an attack, but its effectiveness declines with the duration of inflammation. Moreover, when used to treat an acute attack, colchicine causes adverse GI effects, particularly diarrhea and vomiting, in 80% of patients.
    • To treat an acute attack colchicine is given orally at 0.5-0.6 mg every hour until the patient has relief, has adverse GI effects, or takes 6 mg (ten 0.6-mg tabs). The total dose and the frequency need to be reduced in patients with renal or hepatic insufficiency, and colchicine generally is not recommended in these situations.
    • Patients 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 also should 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 can be seen with pseudogout, sarcoid arthropathy, psoriatic arthritis, and calcific tendonitis.
    • Colchicine also can be administered intravenously. While this route of therapy can quickly abort an attack of gout, it should be employed only in unusual circumstances because it is potentially toxic. Indeed, this therapy is banned in some countries due to a 2% fatality rate. IV colchicine should be used cautiously, if at all, in patients with renal insufficiency or hepatic dysfunction.
    • When given intravenously, 1 mg of colchicine is diluted in 20 mL of isotonic sodium chloride solution without glucose and pushed over 10-20 minutes in a secure IV line. A maximum of 4 mg is given over 24 hours, and no further colchicine should be given for the next week.
    • If the medication extravasates, it can cause tissue necrosis. Within the vessels, it also can cause thrombophlebitis.
    • Granulocytopenia is a prime complication of IV colchicine. The WBC count should be measured before infusion.
    • Other complications include disseminated intravascular coagulopathy, renal failure, hepatocellular toxicity, seizures, and shock.
• Prophylaxis to prevent 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%.
  • The standard dose for prophylaxis is colchicine at 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 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.
  • In patients who cannot take colchicine, NSAIDs can be used for prophylaxis, such as indomethacin at 25 mg bid.
  • Prophylaxis with colchicine can be started during the acute attack.
• Lowering uric acid levels
• • 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 and synovium, even without episodes of acute inflammation.
  • Some rheumatologists advocate waiting for the second attack to begin therapy to lower uric acid levels because not all patients have a second attack and because some patients may need to be convinced they need life-long therapy. This decision is partly dependent on the baseline serum uric acid levels (a level > 9 mg/dL denoting higher risk for recurrent gouty arthritis and tophi).
  • In all cases, the risks and benefits need to be judged based on the individual patient. For instance, in an elderly patient with multiple medical problems and renal insufficiency, the risks of therapy to lower uric acid levels may outweigh the benefits.
  • The goal of therapy is to lower serum uric acid levels to approximately 5-6 mg/dL.
  • 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.
  • Treating patients with colchicine alone 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.
  • While using agents that lower uric acid is important, they should not be started 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 colchicine to prevent another attack.
  • If the patient develops a flare of gout when starting on agents that lower uric acid, do not discontinue the agent because this will only cause another flux in the uric acid level that 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 the majority of middle-aged, otherwise healthy men with gout.
    • Indications for the use of allopurinol instead of probenecid include renal insufficiency (GFR <50 mL/min), renal stones, use of aspirin (blocks the effect of probenecid), overproduction of uric acid, and unresponsiveness to probenecid.
    • Drug interactions may occur with probenecid (see Medications).
    • Patients using probenecid need to drink 2 L of fluid daily at the inception of therapy to ensure adequate diuresis to decrease the risk of renal stones.
  • Sulfinpyrazone: Sulfinpyrazone is an alternative uricosuric agent that has antiplatelet activity but is seldom used because of the added risk of bone marrow suppression.
  • Allopurinol
  • • Allopurinol blocks xanthine oxidase and thus reduces the generation of uric acid. Therefore, it should be used in patients who are overproducers of uric acid and in patients at risk of tumor lysis syndrome to prevent renal toxicity during therapy for malignancies. It is the most effective agent to lower serum uric acid levels. However, alcohol can interfere with the effectiveness of allopurinol.
    • Approximately 3-10% of patients taking allopurinol develop dyspepsia, headache, diarrhea, or pruritic maculopapular rash. More infrequently, patients can develop allopurinol hypersensitivity, which has 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 often are 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.
    • Allopurinol should be discontinued in patients who develop a rash. In patients with a history of drug eruptions due to allopurinol, both an oral (Fam, 2001) and IV (Walz-LeBlanc, 1991) desensitization regimen are available that can be considered.
    • In most patients, start at 100 mg per day and adjust the dose monthly according to the uric acid level until the goal of a uric acid level of 5-6 mg/dL is achieved.
    • Beware of drug interactions. For example, allopurinol prolongs the half-life of azathioprine and 6-mercaptopurine. It enhances the toxicity of cyclophosphamide. Patients taking concomitant ampicillin have an increased incidence of rash.
    • Once the target 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 potential therapeutic options include the following:
  • • Nonrecombinant urate-oxidase (uricase) is used in Europe to prevent severe hyperuricemia induced by chemotherapy in malignant patients, as well as for selected patients with treatment-refractory gout. Recently, the Food and Drug Administration (FDA) approved recombinant Aspergillus flavus uricase for the prevention of tumor lysis syndrome. However, it is highly immunogenic and may cause anaphylaxis.
    • Patients with allopurinol hypersensitivity can often tolerate oxypurinol, which is a metabolite of allopurinol.
    • 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 for patients with gout. It is orally administered and 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.
    • 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.
    • Vitamin C, with its uricosuric effect, may reduce the serum concentration of uric acid.

Surgical Care

• If diagnosed and treated early, patients should not need orthopedic surgery. In patients who are untreated or in those who are treated late in the course of their disease, 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 for gout.

Consultations

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

Diet

• Diet modifications can only improve the serum uric acid levels by 1 mg/dL and rarely are able to lower uric acid levels sufficiently to prevent further attacks and accumulation of uric acid.
• Patients should avoid alcohol because it elevates 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.
• 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 should avoid using the inflamed joint during the acute attack. Otherwise, they should be active.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Acute inflammation from gout can be treated with NSAIDs, corticosteroids, or, rarely, colchicine. NSAIDs generally are the drugs of choice unless the patient has a risk factor that prevents using 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 beginning such therapy.

Drug Category: Nonsteroidal anti-inflammatory drugs

Drugs of choice to treat acute inflammation of gout in patients who can safely take these medications.

Drug Category: Anti-inflammatory agents

Colchicine can be used to treat acute flares of gout but has an 80% risk for diarrhea and vomiting when used in this manner. More often, it is used at a lower dose as a prophylaxis agent to prevent flares of gout when adding agents that lower uric acid.

Drug Category: 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 generally is well tolerated and not associated with the chronic adverse effects seen with long-term steroid use. In many patients, a short course of steroids is the safer option compared to NSAIDs and colchicine. In patients with only 1 or 2 involved joints, intra-articular corticosteroids are a safe and effective treatment option.

Drug Category: Uricosuric agents

Lower uric acid levels by increasing net renal excretion of uric acid. 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.

Drug Category: Xanthine oxidase inhibitors

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 has 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.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

• After the diagnosis and treatment of the episode of acute gouty arthritis, the patient should return to the office in approximately 1 month to be evaluated for therapy to lower serum uric acid levels. If uric acid–lowering therapy is begun, patients should be seen every 1-2 months while adjusting the dose of medications to achieve the target uric acid level of 5-6 mg/dL. Once this level is achieved and maintained, patients can be seen every 6-12 months.

Deterrence/Prevention

• Avoiding alcohol and avoiding obesity may help deter or prevent gout.

Complications

• Untreated, gout can lead to severe joint destruction.
• In those undergoing treatment, the primary problems are toxicity of the medications.
• Septic arthritis can occur in a gouty joint, and draining tophi can become secondarily infected.

Prognosis

• If treated early and properly and if patient compliance is good, the prognosis is excellent.

Patient Education

• Pamphlets on gout are available from the Arthritis Foundation. If appropriate, patients should be counseled on the use of alcohol and a low-fat diet.
• For excellent patient education resources, visit eMedicine's Arthritis Center. Also, see eMedicine's patient education article Gout.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• The major pitfall is not establishing a crystal diagnosis of gout. This is relatively easy to do and provides a clear reason to use life-long medications, such as allopurinol, that have potentially serious adverse effects.
• Patients who present with an acute inflammatory arthritis need to undergo arthrocentesis to exclude septic arthritis, even if their serum uric acid level is elevated. Nongonococcal infectious arthritis has a 10% fatality rate and therefore must be excluded.
• Under normal circumstances, patients should not be treated indefinitely with colchicine only. Synovial tophi will continue to grow and disrupt cartilage and bone. To prevent recurrent flares, patients should be given an agent that lowers uric acid, unless a contraindication exists.
• Do not start therapy with an agent that lowers uric acid during the acute attack because doing so may intensify and prolong the attack.
• Colchicine, even in prophylactic doses, can cause marrow toxicity and neuromyopathy in the setting of renal insufficiency.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Gout. Acute podagra due to gout in an elderly man.
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Media file 2:  Gout. Tophaceous deposits in ear.
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Media file 3:  Gout. Tophaceous deposits on elbow.
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Media file 4:  Gout. Chronic tophaceous gout in an untreated patient with end-stage renal disease.
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Media file 5:  Gout. Fluid obtained from a tophaceous deposit in a patient with gout.
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Media file 6:  Gout. Strongly negative birefringent, needle-shaped crystals diagnostic of gout obtained from an acutely inflamed joint.
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Media file 7:  Gout. Plain radiograph showing typical changes of gout in the first metatarsophalangeal joint and fourth interphalangeal joint.
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Media type:  X-RAY

Media file 8:  Gout. Plain radiograph showing chronic tophaceous gouty arthritis in the hands.
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Media type:  X-RAY

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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• Terkeltaub R, Martin J, Curtiss LK. Apolipoprotein B mediates the capacity of low density lipoprotein to suppress neutrophil stimulation by particulates. J Biol Chem. Nov 25 1986;261(33):15662-7. [Medline].
• Terkeltaub RA, Dyer CA, Martin J. Apolipoprotein (apo) E inhibits the capacity of monosodium urate crystals to stimulate neutrophils. Characterization of intraarticular apo E and demonstration of apo E binding to urate crystals in vivo. J Clin Invest. Jan 1991;87(1):20-6. [Medline].
• Wallace SL, Singer JZ, Duncan GJ. Renal function predicts colchicine toxicity: guidelines for the prophylactic use of colchicine in gout. J Rheumatol. Feb 1991;18(2):264-9. [Medline].
• Walz-LeBlanc BA, Reynolds WJ, MacFadden DK. Allopurinol sensitivity in a patient with chronic tophaceous gout: success of intravenous desensitization after failure of oral desensitization. Arthritis Rheum. Oct 1991;34(10):1329-31. [Medline].
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Article Last Updated: Apr 12, 2006