Sections

Treatment

Approach Considerations

Gout is managed in the following 3 stages^[137]:

Treating the acute attack
Providing prophylaxis to prevent acute flares
Lowering excess stores of urate to prevent flares of gouty arthritis and to prevent tissue deposition of urate crystals

The American College of Rheumatology (ACR) published guidelines on the treatment and prophylaxis of acute gouty arthritis and the management of hyperuricemia.^{[138, 139, 140]} While those guidelines do describe treatment targets, more recent publications have focused more closely on the treat-to-target concept, although for the most part these recommendations are based on underlying principles and expert opinion rather than trial data.^{[141, 142]}

As a general rule, asymptomatic hyperuricemia should not be treated, though ultrasonographic studies have demonstrated that urate crystal deposition into soft tissues occurs in a minority of patients with asymptomatic hyperuricemia.^{[122, 126]}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.^[38]

Urate-lowering therapy appears to reduce the incidence of kidney damage in gout.^[143]In a retrospective study of 16,186 patients with initial serum uric acid levels above 7 mg/dL, Levy and colleagues found that patients with gout who remained on urate-lowering therapy were less likely to develop kidney damage leading to chronic kidney disease than those who were untreated.^[143]All patients were followed for 36 months from their first documented high serum uric acid level.

Patients who achieved a serum uric acid level below 6 mg/dL had a 37% improvement in renal outcomes (P< 0.0001).^[143]The hazard ratio for kidney damage was 1.08 (95% confidence interval, 0.76–1.52) in patients who received urate-lowering therapy more than 80% of the time and was 1.27 (95% confidence interval, 1.05–1.55) in those who received urate-lowering therapy less than 80% of the time.

In a study of gout flares in patients newly started on urate-lowering therapy, Rashid et al found that 68% of these patients had one or more gout flares during the first 12 months of therapy.^[144]Patients 65 years of age and older were more likely to have three or more flares. Other risk factors for gout flares included the following:

Male gender
Failure to attain serum uric acid goal
Presence of three or more comorbidities
Use of diuretics
No changes in initial urate-lowering therapy dose
Nonadherence to urate-lowering therapy

In addition, Hu et al reported that an elevated serum level of cancer antigen 72-4 (CA72-4)—a monoclonally-identified glycoprotein that has been noted to be elevated in adenocarcinomas and inflammatory diseases—is an independent risk factor for gout flares during initiation of urate-lowering therapy. In their prospective study in 193 men, the cumulative incidence of at least one gout flare was 62.1% in the high CA72-4 group (n = 79) versus 38.4% in the normal CA72-4 group (n = 114), and the incidence of two or more flares was 47.1% in the high CA72-4 group versus 23.2% in the normal CA72-4 group (P < 0.001 for both single and recurrent flares).^[145]

The risk of gout flares emphasizes the importance of providing close coverage, patient education, and prophylaxis, especially during the first year of urate-lowering therapy.

Tophi should not be surgically removed unless they are in a critical location or drain chronically. 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.

An international working group has developed treat-to-target recommendations for gout. In the absence of randomized trials comparing standard treatment with treat-to-target approaches in gout, the recommendations were based on indirect evidence and expert recommendations.^[146]The treatment targets are as follows:

Serum uric acid levels reduced below 6 mg/dL (5 mg/dL in patients with severe gout, such as tophi or frequent attacks) and maintained there
Tophi reduced in number or size
Pain reduction
Absence of attacks

Patients should have regular monitoring (eg, every 3-6 months) to assess whether targets are being met.

Treatment of the acute phase of pseudogout is identical to that of acute gout. In patients with idiopathic pseudogout, a deterrent regimen of colchicine may be used. If an underlying metabolic problem is responsible for pseudogout, addressing the underlying problem may result in cure of the arthritis.

Treatment of Acute Attacks

The temptation to treat patients without a proven diagnosis must be resisted. Septic arthritis may clinically resemble gout or pseudogout, and unrecognized septic arthritis can lead to loss of life or limb. Distinguishing septic arthritis from crystal-induced arthritis is not possible without an examination of joint fluid.

Acute treatment of proven crystal-induced arthritis is directed at relief of the pain and inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, colchicine, adrenocorticotropic hormone (ACTH), and anakinra are treatment options. The choice is based primarily on whether the patient has any concomitant health problems (eg, renal insufficiency or peptic ulcer disease). Colchicine, a classic treatment, is now rarely indicated. Local application of ice may help relieve pain in affected joints.^[147]

In patients with a gout flare, the multicenter open-label randomized CONTACT trial found no significant difference in pain relief over 7 days with naproxen versus low-dose colchicine. However, naproxen caused fewer side effects. In CONTACT, adults with a gout flare (n = 399) received either naproxen, 750 mg immediately then 250 mg every 8 hours for 7 days, or low-dose colchicine, 500 mcg three times per day for 4 days. During days 1–7, diarrhea (45.9% vs 20.0%) and headache (20.5% vs 10.7%) were more common in the colchicine group than the naproxen group but constipation was less common.^[148]

When comorbid conditions limit the use of NSAIDs or colchicine, a preferred option may be an intra-articular steroid injection, particularly when a large, easily accessible joint is involved. Septic arthritis must be reasonably excluded.

Therapy to control the underlying hyperuricemia generally is contraindicated until the acute attack is controlled (unless kidneys are at risk because of an unusually heavy uric acid load). Starting therapy to control hyperuricemia during an acute attack may intensify and prolong the attack. If the patient has been on a consistent dosage of probenecid or allopurinol at the time of the acute attack, however, the drug should be continued at that dosage during the attack.

Furthermore, control of hyperuricemia generally is not pursued for a single attack. If attacks are recurrent or evidence of tophaceous or kidney disease is present, therapy for control of hyperuricemia is indicated.^{[149, 150, 151]}

Nonsteroidal anti-inflammatory drugs

NSAIDs are the drugs of choice in most patients with acute gout who do not have underlying health problems. Although indomethacin is the NSAID traditionally chosen for acute gout, most of the other NSAIDs can be used as well. Select an agent with a quick onset of action. Results of a systematic review and meta-analysis suggested that acetic acid–derivative NSAIDs (eg, indomethacin, diclofenac, ketorolac, sulindac) may be superior to ibuprofen NSAIDs for treatment of gout flares.^[152]

Do not use aspirin, because it can alter uric acid levels and potentially prolong and intensify an acute attack. Low-dose aspirin alters uric acid levels, increasing the risk of gout attacks and requiring close uric acid monitoring when aspirin is added to a uric acid/gout treatment regimen.^[153]

Cyclooxygenase-2 (COX-2) inhibitors have been used with success, but patients may require higher dosages than are typically used.^[154]

Avoid NSAIDs in patients with a history of peptic ulcer disease or gastrointestinal (GI) bleeding, those with kidney insufficiency or abnormal liver function, those taking warfarin (a selective COX-2 inhibitor can be used), and those in the intensive care unit (ICU) who are predisposed to gastritis. Limit NSAID use in elderly patients, because of the potential for adverse central nervous system (CNS) effects. Use NSAIDs cautiously in patients with diabetes and those who are receiving concomitant angiotensin-converting enzyme (ACE) inhibitors.

To control the acute attack, NSAIDs are prescribed at full dosage for 2-5 days. Once the acute attack is controlled. the dosage is reduced to approximately one half to one fourth of that amount. Taper the dosage over approximately 2 weeks. Gout symptoms should be absent for at least 2 days before the NSAID is discontinued.

Colchicine

Although colchicine was once the treatment of choice for acute gout, it is now less commonly used than NSAIDs because of its narrow therapeutic window and risk of toxicity.^{[155, 156]}To be effective, colchicine therapy is ideally initiated within 36 hours of onset of the acute attack. When used for acute gout in classic hourly dosing regimens (no longer recommended), colchicine causes adverse GI effects, particularly diarrhea and vomiting, in 80% of patients.

Dosing recommendations for colchicine in the treatment of acute gout have undergone modifications as awareness of its toxicities has increased. Newer recommendations trend toward lowered daily and cumulative doses.^{[155, 157]}

The regimen currently favored consists of 1.2 mg of oral colchicine, followed by 0.6 mg 1 hour later to initiate treatment of the early gout flare. In a multicenter, randomized, double-blind, placebo-controlled, parallel-group study, Terkaltaub et al found that this regimen yielded both maximum plasma concentration and early gout flare efficacy comparable with those of high-dose colchicine (4.8 mg total over 6 hours), with a safety profile indistinguishable from that of placebo.^[158]

Data from 7 separate drug-to-drug interaction (DDI) studies suggests colchicine dose reductions of 33-66% for treatment of acute gout and 50-75% for prophylaxis when colchicine is given in combination with the extended-release calcium channel blockers verapamil and diltiazem or with the numerous P-gp and/or CYP3A4 inhibitors (eg, clarithromycin and cyclosporine); in addition, patients should avoid grapefruit juice. Dosages of colchicine did not have to be adjusted when the drug was used in combination with azithromycin.^[159]

Colchicine should generally be avoided if the glomerular filtration rate (GFR) is lower than 10 mL/min, and the dose should be decreased by at least half if the GFR is lower than 50 mL/min. Colchicine should also be avoided in patients with liver dysfunction, biliary obstruction, or an inability to tolerate diarrhea.

A clinical response to colchicine is not pathognomonic for gout. Responses may also occur in patients with pseudogout, sarcoid arthropathy, psoriatic arthritis, or calcific tendonitis.

In 2008, the US Food and Drug Administration (FDA) ruled that intravenous (IV) colchicine can no longer be produced or shipped in the United States, because of its toxicities. Consequently, IV colchicine is no longer advocated for the treatment of acute gout in the United States.^[160]

Corticosteroids

Corticosteroids can be given to patients with gout who cannot use NSAIDs or colchicine. Steroids can be given orally, IV, intramuscularly (IM), or intra-articularly. Using parenteral corticosteroids confers no advantage unless the patient cannot take oral medications.

Prednisone can be given at a dose of approximately 40 mg for 1-3 days, which is then tapered over approximately 2 weeks (tapering more rapidly can result in a rebound flare). Monitor closely for corticosteroid effects. If treatment continues for more than 2 weeks, consider measures to prevent osteoporosis.

Intra-articular long-acting (depot) 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 before injecting intra-articular corticosteroids is particularly important.

An alternative to corticosteroid administration is to give ACTH (40 IU subcutaneously, with repeat dosing as needed) to induce production of corticosteroid by the patient’s own adrenal glands. Such a regimen does not depend on the patient for proper tapering of prednisone.

Canakinumab

In August 2023, the FDA approved canakinumab for gout flares in adults in whom NSAIDs and colchicine are contraindicated, are not tolerated, or do not provide an adequate response, and in whom repeated courses of corticosteroids are not appropriate. Canakinumab is a monoclonal antibody that binds to human interleukin (IL)-1β and neutralizes its activity by blocking its interaction with IL-1 receptors. In clinical trials over the past decade, pain relief was better with canakinumab than with active comparators.^{[161, 162]}

Combination therapy

If the patient does not have an adequate response to initial therapy with a single drug, ACR guidelines advise that adding a second appropriate agent is acceptable. Using combination therapy from the start is appropriate for an acute, severe gout attack, particularly if the attack involves multiple large joints or is polyarticular. Acceptable regimens include any of the following, in full or prophylactic doses as appropriate^[139]:

Colchicine plus NSAIDs
Oral corticosteroids plus colchicine
Intra-articular steroids plus colchicine or NSAIDs

Anakinra

Desmarais and Chu reported that anakinra (Kineret), an interleukin-1 receptor antagonist that is primarily indicated for rheumatoid arthritis, is an effective and safe treatment for acute gout and pseudogout in hospitalized patients, particularly those with comorbidities that limit treatment choices. In their study of hospitalized patients with acute gout (n = 77), pseudogout (n = 11), or both (n = 3), 92% of gout flares and 79% of pseudogout flares responded to treatment. Patients tolerated anakinra well.^[163]

A systematic review by Cipolletta et al supported the use of anakinra for CPPD, especially in acute refractory cases or when standard treatments are contraindicated. Clinical response to anakinra was reported in 80.6% of patients with acute CPPD. Short-term treatment was well tolerated; adverse events were reported in 4.1% of cases.^[164]

Treatment of Chronic Gout

When a patient experiences a first attack of gout, any medication regimens that may have contributed to the gout attack must be altered, and any predisposing medical conditions or habits must be addressed.^[165]Patients should be instructed to go on a diet if obese, to stop drinking beer, and to avoid purine-rich foods.

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. If the first attack is not severe, however, some rheumatologists advocate waiting for a second attack before initiating such therapy; not all patients experience a second attack, and some patients may require convincing that they need lifelong 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).

ACR guidelines strongly recommend pharmacologic urate-lowering therapy for patients with gout who have 1 or more subcutaneous tophi on clinical examination, evidence of damage on an imaging study, or frequent attacks of acute gouty arthritis (2 or more attacks per year); once the target level has been achieved, uric acid should be monitored at 6-month intervals.^[166] The ACR conditionally recommends pharmacologic urate-lowering therapy for patients with chronic kidney disease of stage 3 or worse, a serum uric acid concentration > 9 mg/ dL, or urolithiasis.^[140]

Long-term management of gout is focused on lowering uric acid levels. The goal of therapy is to reduce serum uric acid levels to below 6 mg/dL, at minimum. In many cases, lowering uric acid levels to less than 5 mg/dL is necessary to improve the signs and symptoms of gout. ACR guidelines recommend that once palpable tophi and all acute and chronic gout symptoms have resolved, urate-lowering therapy should be continued indefinitely, if it is well-tolerated and not burdensome.^[140]

Perez-Ruiz et al have proposed that once dissolution of existing urate crystals has been achieved, less stringent control may suffice to prevent formation of new crystals.^[167]In their prospective cohort study of 211 patients from whom urate-lowering therapy was withdrawn either after 5 years if no tophus was present at baseline or 5 years after resolution of the last tophus, no patient who maintained an average serum urate level lower than 7 mg/dL developed a crystal-proven recurrence of gout.

Controversially, a 2016 guideline from the American College of Physicians (ACP) does not recommend the "treat to target" approach to controlling serum uric acid levels. The ACP concluded that evidence was insufficient to determine whether the benefits of escalating urate-lowering therapy to reach a serum urate target outweigh the harms associated with repeated monitoring and medication escalation.^{[168, 169]}

A 2-year double-blind randomized trial of serum urate–lowering therapy in 104 patients with erosive gout compared treatment with an intensive serum urate target of < 0.20 mmol/L (3.36 mg/dL) versus a standard target of < 0.30 mmol/L (5.04 mg/dL). Patients in the intensive target group achieved significantly lower serum urate levels, but they were less likely to achieve the target level by year 2, (62% versus 83% of patients in the standard target group) and they had a higher medication burden. Both groups showed similar improvement in clinical measures, and similar small increases in bone erosion scores.^[170]

Avoiding the use of medications that elevate uric acid in patients with gout is prudent. Thus, in patients with hypertension, other agents are preferable to a thiazide diuretic, provided that blood pressure can be managed easily with a single drug. Low-dose aspirin is also anti-uricosuric. The angiotensin-receptor blocker (ARB) losartan should be considered, because it is uricosuric at 50 mg/day. However, medications that elevate uric acid can still be used, if required, by making appropriate adjustments of allopurinol or probenecid doses.

Urinary excretion amounting to less than 800 mg per 24-hour period on an unrestricted diet is considered underexcretion. Underexcreting patients are candidates for uricosuric therapy with probenecid. The dosage is increased at monthly intervals until the uric acid level is lowered to target. Urinary alkalization (eg, with potassium citrate) and ingestion of copious amounts of fluid are adjunctive recommendations.

In patients with gout who have moderate to severe kidney disease, ACR guidelines recommend xanthine oxidase inhibitor therapy with either allopurinol or febuxostat as the first-line pharmacologic approach. Probenecid can be used in patients who have contraindications to or are intolerant of at least 1 of those first-line agents, or it may be combined with a xanthine oxidase inhibitor if the inhibitor does not lower uric acid sufficiently.^{[138, 140]}Probenecid could also be used for those patients who consider the risks of xanthine oxidase inhibitors to be too high.

Fralick et al reported that in patients with type 2 diabetes mellitus who were treated with sodium-glucose cotransporter 2 (SGLT2) inhibitors, which prevent the reabsorption of glucose and lower serum uric acid levels, the incidence of gout was approximately 40% lower than in patients treated with glucagonlike peptide–1 receptor (GLP-1) agonists. Their population-based study, in 295,907 adults with type 2 diabetes mellitus, found that the gout incidence rate in patients who were newly prescribed an SGLT2 inhibitor was 4.9 events per 1000 person-years, compared with 7.8 events per 1000 person-years in those newly prescribed a GLP-1 agonist (hazard ratio 0.64, 95% confidence index [CI], 0.57 to 0.72; rate difference per 1000 person-years, −2.9, 95% CI −3.6 to −2.1).^[171]

Prophylaxis

Because allopurinol, febuxostat, and probenecid change serum and tissue uric acid levels, they may precipitate acute attacks of gout. To reduce this undesired effect, colchicine or low-dose NSAID treatment is provided for at least 6 months. In patients who cannot take colchicine or NSAIDs, low doses of prednisone can be considered. When used prophylactically, colchicine can reduce such flares by 85%.^[172]Patients with gout may be able to abort an attack by taking a single colchicine tablet at the first twinge of an attack.

The standard dosage of colchicine for prophylaxis is 0.6 mg twice daily, but lower dosages have also been suggested. Significant dosage reduction is critical for patients who are also taking calcium channel blockers (eg, verapamil or diltiazem) and any of the large number of P-gp or CYP3A4 inhibitors (eg, clarithromycin or cyclosporine). In patients with kidney insufficiency, the dosing frequency may have to be decreased to once daily or every other day.

Adverse GI effects are uncommon with this dosage, occurring in only 4% of patients. This stands in contrast to the 80% risk of adverse GI effects with the classic hourly colchicine regimen for the treatment of acute gout.

Even in prophylactic doses, however, long-term use of colchicine can lead to marrow toxicity and to neuromyopathy, with elevated levels of creatine kinase and resulting muscle weakness. Colchicine-induced neuromyopathy is a particular risk in patients with kidney insufficiency.^[173]

If the patient develops a gout flare after beginning therapy with a uric acid–lowering agent, the agent should not be discontinued, because discontinuance will only cause another flux in the uric acid level, which may prolong and intensify the attack.

Allopurinol

Allopurinol blocks xanthine oxidase and thus reduces the generation of uric acid. Approximately 3-10% of patients taking allopurinol develop symptoms of intolerance, such as dyspepsia, headache, diarrhea, or pruritic maculopapular rash. Allopurinol should immediately be discontinued in patients who develop pruritus or a rash consistent with allopurinol hypersensitivity.

Less frequently (1% of cases), patients taking allopurinol can develop severe allopurinol hypersensitivity syndrome, which carries a mortality of 20-30%.^[174]Features of this syndrome include fever, toxic epidermal necrolysis, bone marrow suppression, eosinophilia, leukocytosis, kidney failure, liver failure, and vasculitis. Corticosteroids are often used to treat severe allopurinol hypersensitivity syndrome.

Severe allopurinol hypersensitivity syndrome may present as Stevens-Johnson syndrome or as drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. DRESS syndrome affects the liver, kidney, and skin. It is a delayed-hypersensitivity response occurring 6-8 weeks after initiation of allopurinol. The underlying mechanism is thought to be a cell-mediated immune reaction to allopurinol and its metabolites. Although the frequency is only is 0.4%, the rate of organ failure and death is high. Treatment is with IV N-acetylcysteine and steroids.

Severe allopurinol hypersensitivity syndrome is more likely to occur in patients with renal insufficiency, those who are taking a thiazide diuretic, and those started on allopurinol at a dosage of 300 mg/day.^[175]In addition, strong associations have been found between severe allopurinol hypersensitivity reactions and carriage of the HLA–B*5801 allele.^[176]

ACR guidelines conditionally recommend screening for HLA–B*5801 carriage, using a polymerase chain reaction–based test, in patients of Southeast Asian descent (eg, Han Chinese, Korean, Thai) and in African Americans, but not in patients of other racial or ethnic backgrounds. The ACR strongly recommends starting allopurinol at a daily dose of 100 mg or less, and lower doses in patients with chronic kidney disease.^[140]

A population-based cohort study of 130,325 allopurinol initiators in British Columbia, Canada found that the multivariable relative risk of allopurinol-associated severe cutaneous adverse reactions in patients with heart disease was 1.55 (95% confidence interval 1.01-2.37). Patients with heart disease and chronic kidney disease who were started on an allopurinol dosage of greater than 100 mg/d had an 11-fold higher risk; however, starting allopurinol at a lower dosage resulted in a fivefold reduction in risk. In older women with heart disease from regions with large Asian population (ie, the group with the highest HLA–B*5801 carriage), risk was 23-fold higher than in younger men without heart disease from other regions.^[177]

Given the elevated risk of severe cutaneous reactions to allopurinol in patients with heart disease, it is important to ensure that hyperuricemia is not related to heart disease medication before starting allopurinol. Rather than allopurinol, the patient may simply need modification of the cardiac regimen (eg, reduction or discontinuation of thiazide diuretics).

In most patients, start allopurinol at 100 mg/day (50 mg/day in patients with renal insufficiency). Stamp et al have proposed that the risk of allopurinol hypersensitivity may be reduced by starting allopurinol at a dose of 1.5 mg per unit of estimated GFR.^[178]

Adjust the dosage upward every 2-5 weeks according to the uric acid level until the goal of a uric acid level of 6 mg/dL or less is achieved. Once the target uric acid level has been achieved and maintained for 6 months, discontinue colchicine prophylaxis, unless the patient has 1 or more tophi on clinical exam.

Previously, adjusting the allopurinol maintenance dosage to the creatinine clearance rate was recommended for patients with renal insufficiency. However, Vázquez-Mellado et al found no increase in the prevalence of adverse reactions to allopurinol in patients who were started at an adjusted dosage but subsequently had their dosage raised to meet therapeutic targets.^[179]

ACR guidelines advise that the dosage of allopurinol can be raised above 300 mg/day, even in patients with renal impairment, provided that the patient receives adequate education and monitoring for drug toxicity (including measurement of transaminase levels). The maximum dosage of allopurinol approved by the US Food and Drug Administration (FDA) is 800 mg/day,^[138]but the maximum dosage should be lower in patients with chronic kidney disease.

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.

Allopurinol can be used in combination with probenecid. However, note that probenecid increases the excretion of allopurinol.

In a retrospective 24-month study of gout patients who had been prescribed allopurinol, Riedel et al found that only 18% of them filled all their prescriptions throughout the entire follow-up period and thus were presumably compliant; 10.4% filled only a single prescription.^[180]In contrast, Rees et al reported that when patients receiving urate-lowering therapy were given a predominantly nurse-delivered intervention that included education and individualized lifestyle advice, 92% achieved target serum uric acid levels at 1 year.^[181]

Febuxostat

Febuxostat, a nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol in patients with gout.^{[182, 183]}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 used in patients with renal impairment with no dosage adjustment.^[184]It is more expensive than allopurinol.

The CONFIRMS trial demonstrated the efficacy and safety of febuxostat in lowering hyperuricemia. By 6 months, the primary endpoint—a serum uric acid level of less than 6.0 mg/dL—was achieved in 45% of subjects on febuxostat 40 mg/day, 67% on febuxostat 80 mg/day, and 42% on allopurinol. In subjects with renal impairment, the primary endpoint was achieved in 50% of subjects on febuxostat 40 mg/day, 72% on febuxostat 80 mg/day, and 42% on allopurinol. Adverse event rates were low and similar in all groups.^[185]

In patients aged 65 years or older, the primary endpoint was achieved in 62% on febuxostat 40 mg/day, 82% on febuxostat 80 mg/day, and 47% on allopurinol. These figures remained essentially unchanged in subjects with mild-to-moderate renal impairment.^[186]

In African-American subjects, the primary endpoint was reached in 47% on febuxostat 40 mg/day, 68% on febuxostat 80 mg/day, and 43% on allopurinol. Similar rates were seen in subjects with renal impairment.^[187]Adverse event rates in both subgroups were comparable with those in the overall trial.

The efficacy and safety of febuxostat in women was demonstrated in the CONFIRMS trial and in 2 other trials comparing febuxostat and allopurinol: FACT (Febuxostat Versus Allopurinol Controlled Trial) and APEX (Allopurinol- and Placebo-Controlled, Efficacy Study of Febuxostat). Achievement of a uric acid level below 6.0 mg/dL rose with increasing daily doses of febuxostat doses, from 54.3% in patients receiving 40 mg to 100% in those receiving 240 mg, compared with 45.9% with allopurinol. Results were similar in subjects with renal impairment.^[188]

Stepwise introduction of febuxostat—10 mg/day for 4 weeks, then 20 mg/day for 4 weeks, then 40 mg/day—was found to reduce gout flares, in randomized open-label comparative study by Yamanaka et al.^[189]Although flares still occurred, their frequency was reduced even in the absence of colchicine coverage, so this approach may also be of benefit for individuals with significant contraindications to colchicine or NSAIDs.

White et al reported that all-cause mortality and cardiovascular mortality were higher with febuxostat than with allopurinol (hazard ratio [HR] for death from any cause, 1.22; HR for cardiovascular death, 1.34).^[190]In 2019 the US Food and Drug Administration (FDA) added a black box warning regarding increased risk of death with febuxostat compared with allopurinol. The FDA also limited the approval of febuxostat to use in cases of allopurinol therapeutic failure or intolerance.^[191]

Pegloticase

In 2010, the FDA approved pegloticase, a polyethylene-glycol–conjugated uricase, for chronic gout refractory to conventional therapy. Pegloticase, which enzymatically catalyzes the oxidation of uric acid to allantoin, is an IV biologic agent to be considered when adjustment of contributing medications (eg, diuretics) and treatment with allopurinol, febuxostat, and uricosuric agents are insufficient to achieve appropriate reduction of serum uric acid levels.^[138]Although pegloticase was approved by the European Medicines Agency (EMA), it was withdrawn from the European Union market in 2016 at the request of the marketing authorization holder, for commercial reasons.^[192]

The FDA approved pegloticase in combination with weekly methotrexate in 2022 based on the MIRROR clinical trial. At 6 months, 71% (71 of 100) of patients randomized to receive pegloticase with methotrexate compared with 39% (20 of 52) of patients randomized to receive pegloticase with placebo achieved the primary endpoint (defined as serum uric acid less than 6 mg/dL at least 80% of the time during Month 6) (P < 0.0001).^[193]

Adverse effects of pegloticase include anaphylaxis, infusion reactions, gout flares, and exacerbation of congestive heart failure. At present, its high cost compromises its cost-effectiveness as an initial approach.^[194]The ACR guidelines do not recommend pegloticase as a first-line approach.^[140]

Other uricases

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. Short-term use of such agents in patients with severe tophaceous gout could debulk the total-body urate load, allowing maintenance with probenecid or allopurinol.

Lesinurad

Lesinurad (Zurampic), which is a selective uric acid reabsorption inhibitor, was approved by the FDA in 2017 for treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone. Lesinurad must be coadministered with a xanthine oxidase inhibitor.^[195]The manufacturer discontinued sale of lesinurad in 2019, for business reasons.^[196]

Other therapeutic options

Vitamin C, with its uricosuric effect, may reduce the serum concentration of uric acid. In one study, 500 mg/day for 2 months reduced uric acid by a mean of 0.5 mg/dL in patients without gout.^[197]However, gout patients appear to be less responsive to such a low dose of ascorbate. Vitamin C treatment should be avoided in patients with nephrolithiasis, urate nephropathy, or cystinuria.

Kobylecki et al reported that each 10 µmol/L higher plasma vitamin C level was associated with a 2.3 µmol/L lower plasma urate level. However, carriage of the SLC23A1 genetic variant, which causes lifelong high plasma vitamin C levels, was not associated with plasma urate levels or with risk of hyperuricemia.^[198]

Benzbromarone is an effective uricosuric agent that was never approved for use in the United States because of concerns over hepatotoxicity^[199]; however, it is available in some other parts of the world, including several European countries, New Zealand, Brazil, and parts of Asia.^[200]A prospective, randomized, open-label trial in 196 men with gout and renal uric acid underexcretion (fractional excretion of urate < 5.5% and uric acid excretion ≤600 mg/day/1.73 m²) reported that after 12 weeks, 61% of patients receiving low-dose benzbromarone (25 mg daily) achieved the serum urate target of < 6 mg/dL, compared with 32% of those receiving low-dose febuxostat (20 mg daily)(P < 0.001). Transaminase elevation occurred more often in the febuxostat group than the benzbromarone group (15% vs 4%, respectively), but rates of other adverse events, including gout flares and urolithiasis, did not differ between the groups.^[201]

Fenofibrate, a fibric acid derivative that is approved for treatment of hypercholesterolemia, mixed dyslipidemia, and hypertriglyceridemia. Independently of its effect on lipid levels, fenofibrate lowers serum uric acid concentrations by enhancing urinary excretion of uric acid. However, fenofibrate may produce mild increases in serum creatinine levels.^[202]

Tigulixostat, a nonpurine xanthine oxidase inhibitor, has proved effective and safe for lowering serum urate levels, in a phase II trial.^[203]A phase III trial (EURELIA1) is currently recruiting.

Diet and Activity

Because uric acid is a breakdown product of purine, high-purine foods should be either avoided or consumed only in moderation. Foods very high in purines include the following:

Organ meats such as sweetbreads (eg, pancreas and thymus)
Smelt
Sardines
Mussels

Foods moderately high in purines include the following:

Anchovies
Trout
Haddock
Scallops
Mutton
Veal
Liver
Bacon
Salmon
Kidneys
Turkey

Purines are found in all protein foods. All sources of purines cannot and should not be eliminated.

Overall, purine restriction generally reduces serum uric acid levels by no more than 1 mg/mL, with modest impact, and diets with very low purine content are not palatable. Diet modifications alone are rarely able to lower uric acid levels sufficiently to prevent accumulation of urate, but they may help lessen the triggers of acute gout attacks.

Patients with gout should avoid excess ingestion of alcoholic drinks, particularly beer, because alcohol use elevates uric acid levels and thus 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 increased development of incident gout,^[24]but excesses of any form of alcohol in gout patients are associated with acute gout flares.

Patients should avoid sodas and other beverages or foods sweetened with high-fructose corn syrup. They should also limit their use of naturally sweet fruit juices, table sugar, and sweetened beverages and desserts, as well as table salt.^[138]Patients taking colchicine should avoid grapefruit and grapefruit juice.

Maintaining a high level of hydration with water (at least 8 glasses of liquids per day) may be helpful in avoiding attacks of gout. In view of the association of gout with atherosclerosis, the diagnosis of gout may afford a particularly good opportunity for the clinician to advise a low-cholesterol, low-fat diet if such a diet is otherwise appropriate for the patient. Although a diet of this type 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. Ketosis-inducing diets (eg, fasting) should be avoided, however.

Because acute attacks are already sufficiently limiting of activity, additional limitations of activity are not necessary. The patient should avoid trauma to the affected joint; otherwise, they should be active.

Consultations

Rheumatologists should be involved in the care of patients with difficult gout, as advised in the ACR guidelines. They can establish the diagnosis with arthrocentesis and synovial fluid analysis for crystals. They also are skilled in the management of this disorder, and consultation may be helpful for patients with an acute gout attack that does not respond to NSAIDs within 2 days or to colchicine within 1 day, as well as for patients with refractory hyperuricemia.

Rheumatology or orthopedic consultation is indicated for any patient with septic arthritis or for any patient in whom a septic arthritis cannot be ruled out.

Long-Term Monitoring

After diagnosis and treatment of an acute gouty arthritis episode, the patient should return for a follow-up visit 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 within 2 weeks to ensure that no untoward toxicity has developed and then every 1-2 months while medication dosages are adjusted 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 and their serum uric acid monitored to help assess efficacy and adherence.

Prevention

Diet may affect the risk of developing gout.^[204]A large prospective cohort study in men found that higher adherence to the Dietary Approaches to Stop Hypertension (DASH) diet was associated with a lower risk for gout (adjusted relative risk [RR] for extreme fifths 0.68, 95% confidence interval [CI] 0.57–0.80, P for trend < 0.001), whereas following a typical Western diet was associated with an increased risk for gout (RR 1.42, 95% CI 1.16–1.74, P=0.005).^[205]

The study included 44,444 men with no prior history of gout. On the basis of questionnaire responses, each participant was assigned a DASH dietary pattern score (based on high intake of fruits, vegetables, nuts and legumes, low-fat dairy products, and whole grains, and low intake of sodium, sweetened beverages, and red and processed meats) and a Western dietary pattern score (based on high intake of red and processed meats, French fries, refined grains, sweets, and desserts). Documented gout occurred in 1731 study subjects during 26 years of follow-up.^[205]

As an observational trial, the study could not prove that the DASH diet reduced gout risks. In addition, 91% of the study subjects were white men, and all were health professionals, so the study results may not apply to other racial or socioeconomic groups. Nevertheless, the DASH diet is more palatable than a low-purine diet, and it offers the additional benefits of reducing the risk for cardiovascular disease, stroke, and kidney stones.^{[204, 205]}

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Media Gallery

Gout. Acute podagra due to gout in elderly man.
Gout. Tophaceous deposits in ear.
Gout. Tophaceous deposits on elbow.
Gout. Chronic tophaceous gout in untreated patient with end-stage renal disease.
Gout. Fluid obtained from tophaceous deposit in patient with gout.
Gout. Strongly negative birefringent, needle-shaped crystals diagnostic of gout obtained from acutely inflamed joint.
Gout. Plain radiograph showing typical changes of gout in first metatarsophalangeal joint and fourth interphalangeal joint.
Gout. Plain radiograph showing chronic tophaceous gouty arthritis in hands.
Gout. Radiograph of erosions with overhanging edges.
Gout. Needles of urate crystals seen on polarizing microscopy.
Gout. Hematoxylin and eosin (H&E) stain, low power, showing abundant pale pink areas surrounded by histiocytes and multinucleated giant cells.
Gout. H&E stain, high power, showing that most urate crystals have been dissolved but that some pale brown-gray crystals did survive processing.
Pseudogout. H&E stain, high power, under polarized light to highlight rhomboidal crystals.
H&E stain, medium power, of pseudogout with pale pink fibrocartilage in upper portion and purple crystals of calcium pyrophosphate in lower portion.
Pseudogout. H&E stain, high power, of calcium pyrophosphate crystals, demonstrating their rhomboidal structure.
What is gout? Gout is an inflammatory disease where uric acid precipitates into crystals that deposit in various joints around the body, causing pain and inflammation. This video describes the pathophysiology, causes, symptoms, and treatment of gout.
This wrist radiograph shows chondrocalcinosis of the radiocarpal joint (arrow).
The most common site of calcium pyrophosphate disease (CPPD) involvement, as seen on radiography, is the patellofemoral joint, followed by the radiocarpal joint (shown). Classic radiographic findings are chondrocalcinosis (yellow arrow), hooked osteophytes, and subchondral cysts (red arrow).

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Author

Bruce M Rothschild, MD Professor of Medicine, IU Health; Research Associate, Carnegie Museum

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, The Scientific Research Honor Society, Society of Skeletal Radiology

Disclosure: Nothing to disclose.

Coauthor(s)

Mark L Francis, MD Professor of Medical Education, Department of Medical Education, Paul L Foster School of Medicine, Texas Tech University Health Sciences Center

Mark L Francis, MD is a member of the following medical societies: American College of Physicians, Phi Beta Kappa

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, Phi Beta Kappa

Disclosure: Nothing to disclose.

Additional Contributors

Anne V Miller, MD Chief, Rheumatology Division; Assistant Professor of Internal Medicine, Department of Medicine, Division of Rheumatology, Southern Illinois University School of Medicine

Anne V Miller, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, International Society for Clinical Densitometry

Disclosure: Nothing to disclose.

Acknowledgements

Richard W Allinson, MD Associate Professor, Department of Ophthalmology, Texas A&M University Health Science Center; Senior Staff Ophthalmologist, Scott and White Clinic

Richard W Allinson, MD, is a member of the following medical societies: American Academy of Ophthalmology, American Medical Association, and Texas Medical Association