eMedicine Specialties > Orthopedic Surgery > Systemic Diseases

Gout

Bruce M Rothschild, MD, Professor of Medicine, Northeastern Ohio Universities College of Medicine; Adjunct Professor, Department of Biomedical Engineering, University of Akron; Adjunct Professor, Department of Anthropology, University of Kansas; Director, Arthritis Center of Northeast Ohio

Updated: Feb 27, 2009

Introduction

Background

Gout is an inflammatory arthritis caused by cellular reaction to uric acid crystal deposition.^1,2,3 Usually, gout is hyperacute in presentation, but it may progress to chronic arthritis.

Gout. Radiograph of erosions with overhanging edges.

Gout. Polarizing microscopy needles of urate.

Variation in susceptibility may relate to nitrogen excretory metabolism. Alligators predominantly excrete nitrogen in the form of ammonia (67-87%), aquatic tortoises excrete nitrogen as a mixture of urea and ammonia, Chrysemys turtles excrete nitrogen as urea (24-48%), and Phrynosoma turtles and terrestrial tortoises predominantly excrete nitrogen as uric acid. Dehydration appears especially to predispose animals to gout.

Gout in birds predominantly occurs from renal failure, as the analog of uremia in humans.⁸ Visceral gout basically is a disorder of pericardial and pleuroperitoneal surfaces, whereas synovial gout predominantly produces nodules on the feet. Although osteoclastic resorption has been noted adjacent to such tophi, specific comment is unavailable on bone changes. Synovial gout has been reported in 13 of 2000 parakeets (Melopsittacus undulates)⁹ and 35 of 631 diseased Brown leghorn chickens and observed in a cassowary (Casuarius). Visceral gout, without articular (synovial) gout, has been reported in Ajaia (spoonbill), Cygnus (swan), Touraco (bird; synovial), Anser (goose), Anas (teal), Todorua species, and Casuarius (cassowary).

Urate arthritis or gout was reported in a rabbit but without documentation. Dissociation of visceral and articular gout apparently occurs in at least some mammals, as well as birds. Guanine gout has been reported in swine (which lack guanase),¹⁰ and xanthine deposits have been reported in the spleen, kidneys, and lymph nodes of cattle. Gout has not been reported in anthropoids, although oxalate kidney stones have been noted in Gorilla, Cercopithecus, and Gazella. Dalmatian urate stones may be related to SLC2A mutations, which account for 1.7-5.3% of cases of human gout.¹¹

It is curious that among the dinosaurs, gout has only been found in carnosaurs, in spite of the larger available collections of herbivore skeletons for examination. This may be the result of high levels of uric acid in raptors, in contrast to that in other birds. Gouty arthritis rarely has been noted in crocodilians, lizards, and turtles, but it has been reported in 1-5% of some birds. Contributing factors to occurrence of gout may be red meat in the diet; red meat was perhaps the foundation of the carnosaur diet.¹²

Pathophysiology

Gout can be considered a disorder of metabolism that allows uric acid/urate to accumulate in blood and tissues. When tissues become supersaturated, the urate salts precipitate, forming crystals. Although increase in serum and tissue concentration may allow the crystals to precipitate, the crystals also are less soluble under acid conditions. Any condition predisposing to acidosis also precipitates urate crystals. Urate initially precipitates in the form of needlelike crystals. The light-retarding (phase-shifting) characteristics of urate crystals allow them to be recognized by polarizing microscopy (see Image 2).

Gout. Polarizing microscopy needles of urate.

Frequency

United States

The prevalence of gout in men is 5-13.6 cases per 1000 population; the prevalence in women is 1.5-6.4 cases per 1000 population. The rate is 0.27% in the general population.

Frequency increased 40% from 1990 to 1999.¹³

International

International prevalence of gout is 0.3%.^{14 15} In the Maori people of New Zealand, 10.3% of men and 4.3% of women are affected.^16,17,18

Mortality/Morbidity

• Deposition of uric acid crystal in the kidneys may produce renal failure or obstruction.¹⁹
• Deposition in tissues produces a mass with space-occupying or mass effects. This can produce spinal cord impingement (rarely).
• Joint damage may render the joint nonfunctional.
• Gout is associated with hypertension and coronary artery disease.^20,21

Race

The incidence of gout is 3.11 per 1000 person years in African Americans and 1.82 per 1000 person years in whites.^22,23 In some populations (eg, Chamorros, Maori), frequency of gout is increased; in other populations, it is rarely represented. Frequency is increased in the Blackfoot and Pima.

Sex

• Gout has a 90% male predominance.^24,25
• Gout rarely occurs in women who are premenopausal.

Age

• Gout usually occurs in men older than 20 years. It also occurs in women who are postmenopausal. Gout affects 1.3% of elderly patients.^26,27

Clinical

History

• In hyperacute inflammatory arthritis, symptoms of redness, swelling, heat, tenderness, and interference with range of motion typically are most intense within 24 hours. Tenderness often is so exquisite that the affected individual cannot even tolerate the weight of bed sheets on the affected area. Attacks may be isolated (1-time) events or may occur repeatedly.²⁸
• Deposits forming a lump (tophus) also may be reported.

Physical

Gout usually is an inflammatory arthritis, with symptoms of redness, swelling, reduction of range of motion, and a hot and tender joint. Additional possible findings on physical examination include the following:²⁹

• Gout usually is monarticular, but 5% of cases are polyarticular and may even mimic rheumatoid arthritis.^30,31
• Chronic arthritis with tenderness and swelling, with or without redness, warmth, or joint damage, may be present.
• A tophus deposit may exist in the antihelix of the ear or subcutaneous regions (eg, olecranon, fingertips, cornea, aorta, CNS); an associated finding of a creamy discharge may be present (rarely).
• Other findings may include fever, chills, and carpal tunnel syndrome.
• In monarticular gout, the first metatarsal phalangeal joint is most commonly affected (which leads to the appellation, podagra). Knee and ankle joints are the next most commonly affected, but any joints are susceptible. Polyarticular gout commonly involves the small joints of the fingers and toes, as well as the knees.

Causes

A cellular reaction to uric acid crystal deposition causes gout. Conditions and ingestions that may cause acute changes in the level of uric acid include the following:³²

• Hyperuricemia, including that produced by renal impairment
• Genetic variants in SLC2A transportation
• Reduced-carbohydrate beer
• Obesity
• High fructose corn syrup
• Diabetes
• End-stage renal disease
• Organ transplantations
• Alcohol ingestion
• Dietary excess (especially of anchovies, sardines, sweetbread, kidney, liver, meat extracts)
• Fasting-induced ketosis
• Inborn errors of metabolism
• Lead poisoning (saturnine gout arising from ingestion of moonshine)
• Hypoparathyroidism
• Hyperlipidemia types 2, 4, and 5
• Paget disease
• Hyperproliferative skin disorders (eg, psoriasis)
• Calcium pyrophosphate deposition disease
• Sarcoidosis
• Hemolytic anemia
• Hemoglobinopathies
• Pernicious anemia
• Radiation treatment
• Glycogen storage disease (glycogenosis) type 1
• Down syndrome
• Gut sterilization by antibiotics
• Various medications and other agents, including the following:
  • Cyclosporine³³
  • Aminophylline
  • Caffeine
  • Corticosteroids
  • Cytotoxic drugs
  • Diazepam
  • Diphenhydramine
  • Diuretics
  • L-dopa
  • Dopamine
  • Epinephrine
  • Ethambutol
  • Methaqualone
  • Alpha-methyl dopa
  • Nicotinic acid
  • Probenecid (low dose)
  • Pyrazinamide
  • Salicylates (<10/dL blood levels)
  • Sulfinpyrazone (low dose)
  • Vitamins B-12 and C
  • Sucrose- or fructose-sweetened soft drinks
  • Purine-rich pancreatic therapy for cystic fibrosis

Differential Diagnoses

Other Problems to Be Considered

Type IIA hyperlipoproteinemia
Amyloidosis
Multicentric reticulohistiocytosis
Hyperparathyroidism
Spondyloarthropathy
Sarcoid
Avascular necrosis
Tumor
Infectious arthritides
Malignant soft tissue tumors
Milk-alkali syndrome
Pigmented villonodular synovitis
Pseudogout
Psoriatic arthritis
Reiter syndrome
Renal osteodystrophy
Rheumatoid arthritis

Workup

Laboratory Studies

• Synovial fluid wet mount examination reveals negatively birefringent urate crystals on polarizing examination in 85% of specimens. Synovial fluid WBC count usually is 10,000-70,000/µL, but it may be as low as 1000/µL.
• Peripheral WBC count often is elevated, with left shift during acute attacks.
• Erythrocyte sedimentation rate usually is elevated during acute attacks.
• Hyperuricemia is present in 95% of cases but is not diagnostic.
• Once the acute gout episode is controlled, 24-hour urine uric acid levels also are assessed for choosing medication to control the associated hyperuricemia.

Imaging Studies

• Routine radiographs reveal punched-out erosions or lytic areas with overhanging edges (see Image 1), but generally not within the first year of disease onset. Erosions with overhanging edges generally are considered pathognomonic for gout but also can be found in amyloidosis, multicentric reticulohistiocytosis, and type IIA hyperlipoproteinemia. Erosion with joint space preservation is typical.^34,35

Gout. Radiograph of erosions with overhanging edges.

• MRI depicts gouty tophi, which have low or intermediate signal intensity on T1-weighted spin echo images. Signal intensity also tends to be low on T2-weighted images. In the absence of inflammation, the tophi are sharply delineated. Presence of inflammation results in increased perilesional signal intensity related to inflammation. Tophi and the surrounding area of inflammation enhance with gadolinium.³⁶
• Indium-111–labeled leukocyte scans, usually used to identify infectious foci, also reveal intense accumulation in affected joints in gout.³⁷
• Dual-energy CT, using a renal stone color-coding protocol, assesses chemical composition, labeling urate deposits in red.³⁸

Procedures

• Biopsy findings in synovial membrane or nodules include uric acid crystals if the biopsy is properly processed. As uric acid is water-soluble, the pathologic specimens need to be processed anhydrously.
• Arthrocentesis of the affected joint provides fluid for analysis under polarizing microscopy.

Histologic Findings

Polarizing microscopy reveals negatively birefringent crystals.

Treatment

Medical Care

Treatment of gout is divided into 2 phases — namely, treatment of the acute attack and treatment of the underlying hyperuricemia.

A nonsteroidal anti-inflammatory drug (NSAID) is prescribed at full dosage for 2-5 days to control the acute attack, and the dose is reduced to approximately one half to one fourth of that amount once the acute attack is controlled. The latter is especially important when alteration in uric acid levels or load might be anticipated.

As treatment of the underlying hyperuricemia (lowering of the uric acid levels) actually precipitates gout in up to 50% of individuals, anti-inflammatory therapy is continued (at low doses) for the first 6-18 months of hyperuricemia-directed treatment.

Patient compliance of only 20% indicates that repeated reinforcement of the treatment regimen is necessary.³⁹

• Use of colchicine is controversial because of its toxicity.⁴⁰ Oral administration generally has been discarded, as therapeutic doses usually produce diarrhea, and colchicine therapy must be initiated within 24 hours of onset of the acute attack to be effective. The therapeutic-toxic window is very narrow. The FDA has ordered companies to stop marketing unapproved drug products that contain colchicine in an injectable dosage form.
• Intra-articular long-acting (depot) corticosteroids can be used for single joint involvement if infection is definitely ruled out. Use generally is limited to situations in which nonsteroidal anti-inflammatory agents and colchicine are contraindicated.
• Therapy to control the underlying hyperuricemia generally is contraindicated until the acute attack is controlled (unless kidneys are at risk because of unusual uric acid load). Further, control of hyperuricemia generally is not pursued for a single attack. If attacks are recurrent or evidence of tophaceous or renal disease is present, therapy for control of hyperuricemia is indicated.^41,42,43
  • Any contributing medication regimens are altered first, and any predisposing medical conditions or habits are addressed.⁴⁴
  • The patient then is tested for uric acid excretion. If the patient excretes less than 600 mg of uric acid per 24-hour period on a purine-free diet or less than 800 mg per 24-hour period on an unrestricted diet, the patient is considered a hypoexcreter. Probenecid is administered, and the dosage is increased at monthly intervals until the uric acid is lowered to reference range or at least lowered to 2 mg/dL less than the levels during which attacks were noted.
  • If the patient has tophaceous disease, probenecid should not be used. Urinary alkalization and the recommendation to ingest copious amounts of fluid are adjunctive. If the patient is a hyperexcreter or has tophi or renal disease, the drug of choice is allopurinol.
  • As both probenecid and allopurinol change serum and tissue uric acid levels, they may predispose patients to acute gouty attacks. A low-dose nonsteroidal anti-inflammatory agent is used for 6-24 months to reduce this undesired effect.
• No role exists for probenecid or allopurinol in treatment of an acute gouty attack. If the patient has been on a consistent dose of one of those agents for more than 2 weeks at the time of the acute attack, probenecid or allopurinol should be continued at that dose during the attack.

Consultations

If the gout attack does not respond to nonsteroidal anti-inflammatory agents within 2 days or to colchicine within 1 day, consultation with a rheumatologist may prove helpful. If the hyperuricemia is not controlled, similar consultation may be helpful.

Diet

Treatment adjuvants include weight reduction if the patient has obesity, but ketosis-inducing diets (eg, fasting) should be avoided. As uric acid is a breakdown product of the purine component of DNA, any high-purine foods should be consumed only in moderation. Sweetbread (eg, pancreas, thymus), liver, kidney, brain, meat extracts, meats, and shellfish are high in purine content. Alcohol intake should be minimized. Otherwise, purine restriction reduces serum uric acid levels by only 1 mg/ml, at significant psychological impact. Ingestion of fructose-containing beverages should be reduced, and ingestion of milk and calcium should be increased.⁴⁵ If hyperphosphatemia is present, phosphate-binding agents should be used.

Activity

Because acute attacks are sufficiently limiting to activity, additional limitations of activity are not necessary. The patient should avoid trauma to the affected joint.

Medication

The goals of pharmacotherapy are to reduce morbidity and prevent complications.^{46,47,48,49,50,51,52} Medications are used for frequent or disabling attack, chronic joint disease, tophi, renal insufficiency or recurrent nephrolithiasis, or more than 1100 mg of uric acid excretion per day. Contraindications include sulfa allergy.

RDEA119, a selective, non-ATP competitive inhibitor of the MEK ½ kinases, has shown potential for being a new form of gout treatment.⁵³

Pegloticase (polyethylene glycol-conjugated uricase; 4-8 mg every 2 weeks) also looks to be potentially promising for patients with refractory gout. Complications include flare of gout attacks in 63-86% of patients and nephrolithiasis in 13-14%, along with arthralgias, nausea, dyspepsia, muscles spasms, pyrexia, back pain, diarrhea, and rash.⁵¹

Nonsteroidal anti-inflammatory drugs

Choice of NSAID is more habit than science; use of concomitant misoprostol gastric protection or consideration of a COX-2–specific NSAID might be considered if the patient has gastrointestinal risk; to control the attack as quickly and safely as possible (recalling that it takes 5 half-lives to reach steady state), consider using an NSAID with a short half-life.

Ketoprofen (Oruvail, Orudis)

For relief of mild-to-moderate pain and inflammation. Small doses are initially indicated in small and elderly patients and in those with renal or liver disease. Doses >75 mg do not increase therapeutic effects. Administer high doses with caution, and closely observe patient for response.

Dosing

Adult

25-50 mg PO q6-8h prn; not to exceed 300 mg/d

Pediatric

<3 months: Not established
3 months to 12 years: 0.1-1 mg/kg PO q6-8h
>12 years: Administer as in adults

Interactions

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; monitor PT closely (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently; increases toxicity of lithium

Contraindications

Documented hypersensitivity

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

Caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in patients with history of GI tract bleeding, those with anticoagulation abnormalities, and patients undergoing anticoagulant therapy

Diclofenac (Voltaren, Cataflam)

Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclo-oxygenase, which in turn decreases formation of prostaglandin precursors.

Dosing

Adult

Persistent night pain or morning stiffness: Up to 100 mg PO hs may help to relieve pain; not to exceed total daily dose of 200 mg

Pediatric

Not established

Interactions

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; monitor PT closely (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently

Contraindications

Documented hypersensitivity; administration into CNS; peptic ulcer disease; recent GI tract bleeding or perforation; renal insufficiency (relative contraindication, requiring careful monitoring); high risk for bleeding (unless misoprostol protective coverage)

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 renal failure in patients with preexisting renal disease or compromised renal perfusion; low WBC counts occur rarely and usually return to normal in ongoing therapy; discontinuation of therapy may be necessary if leukopenia, granulocytopenia, or thrombocytopenia persists

Celecoxib (Celebrex)

Inhibits primarily COX-2, which is considered an inducible isoenzyme, induced during pain and inflammatory stimuli. Inhibition of COX-1 may contribute to NSAID GI toxicity. At therapeutic concentrations, COX-1 isoenzyme is not inhibited, thus GI toxicity may be decreased. Seek lowest dose for each patient.

Dosing

Adult

200 mg PO bid

Pediatric

Not established

Interactions

Coadministration with fluconazole may cause increase in plasma concentrations due to inhibition of celecoxib metabolism; coadministration with rifampin may decrease plasma concentrations

Contraindications

Documented hypersensitivity

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

May cause fluid retention and peripheral edema; caution in compromised cardiac function, hypertension, conditions predisposing to fluid retention; severe heart failure and hyponatremia, as may deteriorate circulatory hemodynamics; NSAIDs may mask usual signs of infection; caution in presence of existing controlled infections; evaluate symptoms and signs suggesting liver dysfunction or in abnormal liver lab results

Anti-inflammatories

Reduce formation of uric acid crystals in affected joint, thereby reducing amount of acute inflammation and pain; also decreases uric acid levels in blood.

Colchicine

Can be used in combination with probenecid on a long-term basis to prevent gout or can be used alone to treat pain and inflammation of acute gout attacks. Discontinue when pain of gout attack begins to subside, when maximum dose is reached, or when GI symptoms (eg, nausea, vomiting, diarrhea) indicate cellular poisoning. Decreases leukocyte motility and phagocytosis in inflammatory responses.

Dosing

Adult

0.6 mg PO qh until relief of symptoms or onset of diarrhea; not to exceed 4 mg/d
Not to repeat dose within 6 d; serious damage to GI tract (eg, sloughing of the mucosa) may occur

Pediatric

Not established

Interactions

Sympathomimetic agent toxicity and effect of CNS depressants are significantly increased with colchicine; may decrease vitamin B-12 absorption; coadministration with microtubule active agents (vincristine) not recommended

Contraindications

Documented hypersensitivity; severe renal, hepatic, GI, or cardiac disorders; blood dyscrasias

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Risk of renal failure, hepatic failure, permanent hair loss, bone marrow suppression, numbness or tingling in hands and feet, disseminated intravascular coagulopathy, and decreased sperm count; caution in pregnancy; gastrointestinal intolerance possible

Uricosurics

Reduce uric acid load by blocking metabolism of the purine metabolite xanthine to uric acid.

Note that febuxostat (a thiazolecarboxylic acid derivative, but not a purine base analog) is a potential alternative to allopurinol. Is was approved by the US Food and Drug Administration in February 2009. Common adverse events include upper respiratory tract infections, arthralgias, diarrhea, headache, and liver function abnormalities. Atrioventricular block or atrial fibrillation in 5% and cholecystitis in 2% have also been reported.⁵⁴  Febuxostat physically blocks the channel to the molybdenum-pterin active site of xanthine oxidase and is metabolized by liver oxidation and glucuronidation.¹³ Cardiovascular safety issues have yet to be determined. As with other uricosuric agents, it may precipitate gouty attacks when inititated.^13,54

Losartan (angiotensin II receptor antagonist) is uricosuric at 50 mg/d. Fenofibrate (anti-hyperlipidemic) at 200 mg/d reduces serum urate 19% and increases clearance by 36%. Vitamin C reduces uric acid by 0.5 mg/dL (but should be avoided with nephrolithiasis or urate nephropathy, cystinuria, penicillamine.)

Sulfinpyrazone (Anturane)

Decreases uric acid levels and promotes tophi reabsorption; patients unable to tolerate probenecid are candidates for this drug.

Dosing

Adult

200 mg PO qd; increased by 200 mg at monthly intervals, not to exceed 800 mg/d or until the uric acid is lowered to reference range or at least 2 mg/dL less than the levels present when attacks were noted

Pediatric

Not established

Interactions

Increase effects of anticoagulants; may decrease levels of theophylline, verapamil; coadministration with niacin and salicylates decreases uricosuric activity

Contraindications

Documented hypersensitivity; active peptic ulcer, GI inflammation, blood dyscrasias

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Changes serum and tissue uric acid levels, predisposing to acute gouty attacks; low-dose nonsteroidal anti-inflammatory agent used 6-24 mo to reduce undesired effects; caution in urolithiasis, renal impairment

Probenecid (Benemid)

Used for patients who are hypoexcreters (excrete <600 mg of uric acid/d on purine-free diet or <800 mg/d on unrestricted diet) who do not have kidney stones or tophi.

Dosing

Adult

500 mg PO qd, increased by 500 mg at monthly intervals until uric acid is lowered to reference range or at least 2 mg/dL less than levels present when attacks were noted; not to exceed 3000 mg/d

Pediatric

<2 years: Contraindicated
>2 years: Not established

Interactions

Salicylates at high dosages and nitrofurantoin may decrease effects of probenecid; increases levels/toxicity of methotrexate, beta-lactam antibiotics, acyclovir, thiopental, clofibrate, dyphylline, pantothenic acid, ketorolac, benzodiazepines, rifampin, sulfonamide, dapsone, zidovudine, sulfonylureas

Contraindications

Documented hypersensitivity; known blood dyscrasia or uric acid kidney stones; coadministration of ketorolac as levels/toxicity of ketorolac are significantly increased; renal impairment

Precautions

Pregnancy

B - Usually safe but benefits must outweigh the risks.

Precautions

Crosses placental barrier; use of any drug in women of childbearing potential requires anticipated benefit be weighed against possible hazards; caution in history of peptic ulcer disease; predisposes to acute gouty attacks; low-dose nonsteroidal anti-inflammatory agent used for 6-24 mo to reduce undesired effects

Allopurinol (Zyloprim)

Inhibit xanthine oxidase, the enzyme that synthesizes uric acid from hypoxanthine; reduces the synthesis of uric acid without disrupting the biosynthesis of vital purines.

Dosing

Adult

100 mg PO qd; increase by 100 mg monthly; not to exceed 600 mg/d

Pediatric

<6 years: 150 mg PO qd maximum; assess uric acid levels 48 h after initiation
6-10 years: 300 mg PO qd maximum
>10 years: Administer as in adults

Interactions

Enhanced toxicity of thiazide diuretics, methotrexate, cyclophosphamide, anticoagulant, antidiabetic agents; alcohol decreases effects; increases incidence of skin rash when used concurrently with ampicillin and amoxicillin; large amounts of vitamin C acidify urine and may cause kidney stone formation; allopurinol inhibits metabolism of azathioprine and mercaptopurine (reduce dose to one third usual dosage)

Contraindications

Documented hypersensitivity; bone marrow suppression; liver disease; concomitant cytotoxic drugs

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Not for use in asymptomatic hyperuricemia; reduce dose in renal insufficiency; monitor liver function and perform CBC counts before initiating therapy and periodically thereafter; produces skin rash in 2%; desensitization fails in 50% within 1 year; 5-10% develop transaminitis and central nervous system side effects; major hypersensitivity (rash, fever, hepatitis, eosinophilia and renal failure) rare (0.4%) but has 20% mortality. (Terkeltaub RA, 2008)

Febuxostat (Uloric)

Xanthine oxidase inhibitor. Prevents uric acid production and lowers elevated serum uric acid levels. Indicated for long-term management of hyperuricemia associated with gout.(Schumacher HR Jr, 2009; Terkeltaub RA, 2008)

Dosing

Adult

40 mg PO qd initially; after 2 wk, if serum uric acid levels are not <6 mg/dL, increase to 80 mg/d

Pediatric

Not established

Interactions

Coadministration with xanthine oxidase substrate drugs (eg, azathioprine, mercaptopurine, theophylline) may increase plasma concentration of these substrates, resulting in toxicity

Contraindications

Documented hypersensitivity; coadministration with azathioprine, mercaptopurine, or theophylline

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Increased gout flares frequently observed during initiation of therapy (use prophylactic therapies such as NSAIDs or colchicine); higher rate of thromboembolic events observed in patients treated with febuxostat compared with allopurinol in clinical trials (monitor for signs and symptoms of MI and stroke); may increase liver transaminase levels; common adverse effects include nausea, arthralgia, and rash

Intra-articular corticosteroids

Used for single joint involvement if infection is excluded; water-soluble steroids (eg, Decadron) are teleologically inappropriate for use as a depot steroid treatment.

Triamcinolone (Aristospan Intra-articular, Kenaject)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing capillary permeability.

Dosing

Adult

2.5-40 mg (10 mg/mL or 40 mg/mL formulations) intra-articular, intrasynovial; modify dose according to joint size

Pediatric

Administer as in adults

Interactions

Coadministration with barbiturates, phenytoin, and rifampin decreases effects

Contraindications

Documented hypersensitivity; fungal, viral, and bacterial skin infections

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Multiple complications (eg, severe infections, hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression) may occur; abrupt discontinuation of glucocorticoids may cause adrenal crisis

Corticosteroid stimulating hormones

Stimulate synthesis and release of corticosteroid hormones.

Corticotropin (ACTH, Acthar)

Stimulates endogenous production of corticosteroids. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Dosing

Adult

40 U IM/SC qd/qod

Pediatric

Not established

Interactions

Estrogen coadministration may increase corticosteroid levels; cortisone may increase digitalis toxicity secondary to hypokalemia

Contraindications

Absent adrenal glands; documented hypersensitivity; viral, fungal, or tubercular skin lesions

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Caution in patients with hyperthyroidism, cirrhosis, nonspecific ulcerative colitis, osteoporosis, peptic ulcer, diabetes, and myasthenia gravis

Uric acid oxidizers

Metabolizes uric acid to a soluble form, thus preventing acute renal failure. Estrogens reduce serum uric acid levels 20% in postmenopausal women.¹³

Rasburicase (Elitek)

A recombinant form (derived from Saccharomyces cerevisiae -synthesized, Aspergillus flavus) of the enzyme urate oxidase, which oxidizes uric acid to allantoin. Indicated for treatment and prophylaxis of severe hyperuricemia associated with the treatment of malignancy. Hyperuricemia causes a precipitant in the kidneys, which leads to acute renal failure. Unlike uric acid, allantoin is soluble and easily excreted by the kidneys. Elimination half-life is 18 h.

Dosing

Adult

0.15-0.2 mg/kg/d IV infused over 30 min for 5 d; dilute in 50 mL 0.9% NaCl

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity; G-6-PD deficiency

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

May cause hemolytic anemia secondary to hydrogen peroxide produced during uric acid oxidation; may cause methemoglobinemia; other adverse effects include fever, nausea, or vomiting; children younger than 2 y may experience more vomiting, diarrhea, fever, and rash; avoid shaking or vortexing during product reconstitution; highly antigenic, multiple administration may produce allergic reaction, anaphylaxis, or death; produces false low uric acid levels, accurate levels obtained by collecting blood into prechilled, heparin-containing tubes kept at 4°C and centrifuged at that temperature, maintain resultant plasma at 4°C and analyze within 4 h of collection

Follow-up

Further Outpatient Care

• Serum uric acid levels are assessed at monthly intervals, and dosages of the suppressive agent (eg, probenecid, allopurinol) are modified to achieve goals.
• Surgery may be indicated for tophaceous complications, including infection, joint deformity, compression (eg, cauda equina or spinal cord impingement), and intractable pain, as well as for ulcers related to tophaceous erosions. Delayed healing is noted in 50% of patients. 

Deterrence/Prevention

• Patients should avoid exacerbating medications, diets, and habits when possible^44,14

Complications

• Patients may experience the following complications:
  • Increased susceptibility to infection
  • Urate nephropathy
  • Uric acid nephropathy
  • Renal stones
  • Nerve or spinal cord impingement^55,56

Prognosis

• With early treatment, gout should be totally controlled. If attacks recur, successful uric acid adjustment (requiring lifelong use of uricosuric or allopurinol medication) usually suppresses further activity. During the first 6-24 months of uricosuric or allopurinol therapy, acute gout may occur.^57,58

Patient Education

• Patients with severe hyperuricemia should avoid food with high purine content. Moderation in food and alcohol is advised.
• Early recognition of acute attacks is critical, as intervention with medication is much more effective earlier in the attack.
• For excellent patient education resources, visit eMedicine's Arthritis Center. Also, see eMedicine's patient education article Gout.

Miscellaneous

Medicolegal Pitfalls

• Attentiveness to medication interactions (eg, allopurinol with azathioprine and mercaptopurine) is critical in treatment of hyperuricemia.
• Be alert to the possibility of associated infection complicating or initiating an acute gouty attack.
• Be very circumspect if colchicine is used.

Multimedia

Media file 1: Gout. Radiograph of erosions with overhanging edges.

Media file 2: Gout. Polarizing microscopy needles of urate.

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Keywords

gout, hyperuricemiaurate, crystal arthropathy, podagra, urate deposition disease, inflammatory arthritis, chronic arthritis, bursitis, rheumatoid arthritis

Contributor Information and Disclosures

Author

Bruce M Rothschild, MD, Professor of Medicine, Northeastern Ohio Universities College of Medicine; Adjunct Professor, Department of Biomedical Engineering, University of Akron; Adjunct Professor, Department of Anthropology, University of Kansas; Director, Arthritis Center of Northeast Ohio
Bruce M Rothschild, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Rheumatology, International Skeletal Society, New York Academy of Sciences, Sigma Xi, and Society of Skeletal Radiology
Disclosure: Nothing to disclose.

Medical Editor

Jegan Krishnan, MBBS, FRACS, PhD, Professor, Chair, Department of Orthopedic Surgery, Flinders University of South Australia; Senior Clinical Director of Orthopedic Surgery, Repatriation General Hospital; Private Practice, Orthopaedics SA, Ashford Specialist Centre
Jegan Krishnan, MBBS, FRACS, PhD is a member of the following medical societies: Australian Medical Association, Australian Orthopaedic Association, and Royal Australasian College of Surgeons
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Paul E Di Cesare, MD, FACS, Chair and Professor, Department of Orthopedic Surgery, University of California Davis School of Medicine
Paul E Di Cesare, MD, FACS is a member of the following medical societies: American Academy of Orthopaedic Surgeons, American College of Surgeons, and Sigma Xi
Disclosure: stryker Consulting fee Consulting

CME Editor

Dinesh Patel, MD, FACS, Associate Clinical Professor of Orthopedic Surgery, Harvard Medical School; Chief of Arthroscopic Surgery, Department of Orthopedic Surgery, Massachusetts General Hospital
Dinesh Patel, MD, FACS is a member of the following medical societies: American Academy of Orthopaedic Surgeons, American Association of Physicians of Indian Origin, American College of International Physicians, and American College of Surgeons
Disclosure: Nothing to disclose.

Chief Editor

Harris Gellman, MD, Consulting Surgeon, Broward Hand Center; Voluntary Clinical Professor of Orthopedic Surgery and Plastic Surgery, Departments of Orthopedic Surgery and Surgery, University of Miami School of Medicine
Harris Gellman, MD is a member of the following medical societies: American Academy of Medical Acupuncture, American Academy of Orthopaedic Surgeons, American Orthopaedic Association, American Society for Surgery of the Hand, and Arkansas Medical Society
Disclosure: Nothing to disclose.

Related eMedicine topics

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Hyperuricosuria and Gouty Diathesis

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Rheumatoid Arthritis, Hands

Rheumatoid Arthritis, Spine

Clinical trials

Phase 3, Febuxostat, Allopurinol and Placebo-Controlled Study in Gout Subjects.

Evaluating Efficacy of Canakinumab (ACZ885) in Prevention of Acute Flares in Chronic Gout Patients Initiating Allopurinol Therapy

Re-Exposure Study of Pegloticase Intravenous (i.v.) in Symptomatic Gout Patients

Pegylated Recombinant Mammalian Uricase (PEG-Uricase) as Treatment for Refractory Gout

Pegylated Recombinant Mammalian Uricase (PEG-Uricase) as Treatment for Refractory Gout

Targeted Dose Finding of Canakinumab (ACZ885) for Management of Acute Flare in Refractory or Contraindicated Gout Patients

A Study of RDEA806 in Hyperuricemic Subjects With Symptomatic Gout

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