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Gout: Treatment & Medication
Updated: Feb 20, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
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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.
- Colchicine in acute 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 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 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.
- 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.
Adult
50 mg PO tid or qid for 1-3 d, depending on response, and begin tapering
Pediatric
Not established
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
Documented hypersensitivity, patient on anticoagulation, GI bleeding, renal insufficiency, thrombocytopenia
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.
Adult
PO for acute flares:
1.2 mg PO for first dose, followed by a second dose of 0.6 mg administered 1 h later
Strong CYP3A4 inhibitors: 0.6 mg PO for first dose, then 0.3 mg 1 h later; may repeat no earlier than 3 d
Moderate CYP3A4 inhibitors: 1.2 mg PO once (no second dose); may repeat no earlier than 3 d
P-glycoprotein inhibitors: 0.6 mg PO once (no second dose); may repeat no earlier than 3 d
CrCl <30 mL/min: Administer usual dose, but do not repeat more frequently than q2wk
Hemodialysis: 0.6 mg PO once; do not repeat more frequently than q2wk
Severe hepatic impairment: Administer usual dose, but do not repeat more frequently than q2wk
IV for acute flares: No longer advocated
Prophylaxis: 0.5 mg or 0.6 mg PO bid; adjust dose for renal insufficiency
Pediatric
<18 years: Not established
Cytochrome P450 isoenzyme 3A4 inhibitors (eg, grapefruit juice, clarithromycin, cyclosporine, erythromycin, itraconazole, telithromycin) may significantly increase toxicity; sympathomimetic agent toxicity and effect of CNS depressants significantly increased with colchicine
Documented hypersensitivity; renal or hepatic impairment if using P-glycoprotein or strong cytochrome P450 isoenzyme 3A4 inhibitors (life-threatening and fatal toxicity reported with therapeutic doses); GI or cardiac disorders; blood dyscrasias
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
Inform patients about risk of fatal drug interactions that can occur at prescribed doses and with medications given for short times (eg, antibiotics that are cytochrome P450 isoenzyme 3A4 inhibitors); monitor for signs of toxicity, including muscle numbness/pain (myotoxicity, including rhabdomyolysis), numbness/tingling in extremities, unusual bleeding/bruising (myelosuppression), severe diarrhea/vomiting, weakness/fatigue, increased infections, and pale or grey lips, tongue, or palms; patients should avoid consuming grapefruit and grapefruit juice; caution with severe renal or hepatic impairment (adjust dose)
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.
Adult
Initial: 40 mg PO qd for 1-3 d, depending on response, and tapered over approximately 2 wk
Pediatric
Not established
Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of corticosteroids; monitor for hypokalemia with coadministration of diuretics
Documented hypersensitivity; severe bacterial, viral, or fungal infection; active peptic ulcer disease; diabetes mellitus
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
With long-term use, abrupt discontinuation of corticosteroids may cause adrenal crisis; high doses may cause hyperglycemia, edema, avascular necrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression in children, and infections
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.
Probenecid
Designed to lower tissue stores of uric acid by increasing net renal excretion of uric acid by inhibiting tubular reabsorption. Some authorities recommend alkalizing the urine when starting probenecid to reduce the risk for renal stone formation.
Adult
250 mg PO bid for 1 wk, then 500 mg bid; can increase up to 3 g/d
Pediatric
Not established
Salicylates at high dosages and nitrofurantoin may decrease effects; increases levels/toxicity of methotrexate, beta-lactam antibiotics, acyclovir, thiopental, clofibrate, dyphylline, pantothenic acid, ketorolac, benzodiazepines, rifampin, sulfonamide, dapsone, zidovudine, and sulfonylureas
Documented hypersensitivity; children <2 y; high urinary uric acid excretion, renal insufficiency (GFR <50 mL/min), renal stones; known blood dyscrasia; coadministration of ketorolac because levels/toxicity of ketorolac are significantly increased
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Not for use in asymptomatic hyperuricemia; 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; can provoke attacks of acute gouty arthritis and 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.
Allopurinol (Zyloprim)
Reduces production of uric acid, thereby allowing body to dispose of excess uric acid stores. Most effective therapy to lower serum uric acid. Most patients achieve the target uric acid level of 5 mg/dL at 300-400 mg/d, less if renal insufficiency is present.
Adult
Initial: 100 mg/d PO; titrate monthly according to serum uric acid level
Maintenance: 300-400 mg/d PO
Effective doses based on GFR: 400 mg PO qd for 140 mL/min creatinine clearance; 300 mg for 100 mL/min creatinine clearance; 200 mg for 60 mL/min creatinine clearance; 150 mg for 40 mL/min creatinine clearance; 100 mg for 20 mL/min or less
Pediatric
Not established
Alcohol decreases effects; increases incidence of skin rash when used concurrently with ampicillin and amoxicillin; large amounts of vitamin C acidifies urine and may cause renal stone formation; inhibits metabolism of azathioprine and 6-mercaptopurine
Documented hypersensitivity (if reaction not severe, can try a desensitization regimen).
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 count before initiating therapy and periodically thereafter, discontinue medication if rash occurs and evaluate
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.
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
Coadministration with xanthine oxidase substrate drugs (eg, azathioprine, mercaptopurine, theophylline) may increase plasma concentration of these substrates, resulting in toxicity
Documented hypersensitivity; coadministration with azathioprine, mercaptopurine, or theophylline
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
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References
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Further Reading
Keywords
gout, uric acid metabolism, chronic tophaceous gout, tophaceous gout, gouty arthritis, primary gout, secondary gout, acute gout, chronic gout, pseudogout, polyarticular gout, saturnine gout, hyperuricemia, cyclosporin A, acute monoarticular arthritis, podagra, polyarticular arthritis, uric acid, inflammasome, anakinra, interleukin 1, joint inflammation, joint destruction
