Gout: Update on Therapy

January 2, 2009

Although gout has been recognized since ancient times, its management remains challenging. In a previous article (CONSULTANT, December 2008, page 1010), I focused on diagnosis; here I discuss how the treatment approaches for an acute flare and for chronic gout differ, and I compare the safety and efficacy of available therapies.

Although gout has been recognized since ancient times, its management remains challenging. In a previous article (CONSULTANT, December 2008, page 1010), I focused on diagnosis; here I discuss how the treatment approaches for an acute flare and for chronic gout differ, and I compare the safety and efficacy of available therapies.

The 3 goals of therapy for gout are:
•To terminate the acute painful attack.
•To prevent recurrences by controlling hyperuricemia.
•To prevent or reverse the complications of urate deposition in joints, kidneys, and other sites.1

TREATMENT OF ACUTE GOUT

The earlier anti-inflammatory treatment is started, the more rapidly the acute flare will subside. Ensure adequate dosing, and treat until the flare has resolved. Once all overt signs of inflammation are gone, continue and then taper treatment for at least 2 or 3 days. The choice of an antiinflammatory agent depends on patient age and comorbidities (Table 1).2

NSAIDs. In otherwise healthy patients without significant heart or GI disease or a history of aspirin allergy, NSAIDs are preferred. In more than 90% of patients, attacks resolve within 5 to 8 days of starting therapy.1 Adverse events associated with NSAIDs limit their use. These include worsening of renal function, fluid retention, gastric problems, hepatotoxicity, and impaired cognitive function. In patients with known renal impairment, reduce the NSAID dosage and monitor renal function.3

Colchicine. This agent works best when administered within 24 to 48 hours of the onset of an acute attack. Its effectiveness is reduced once an acute attack has persisted for a few days. Colchicine diminishes symptoms by disrupting chemotaxis and phagocytosis of inflammatory cells. It does not reduce the accumulation of monosodium urate deposits and joint damage in chronic gout, and it should not be used long-term in chronic gout.1,3 Instruct patients to begin taking colchicine at the first sign or symptom of an acute flare to avert a full-blown attack.

Most patients who take colchicine at therapeutic doses experience symptoms of GI toxicity, such as diarrhea, before symptoms abate. Long-term effects include myopathy, but this is rare. Select alternative agents for elderly patients and for those who are receiving dialysis.3 Use colchicine cautiously in patients with liver or renal disease; adjust the dose for those with renal impairment.3

Corticosteroids. Intra-articular, intravenous, intramuscular, and oral corticosteroids have been effective in acute gout.1 They are especially useful when NSAIDs or colchicine are contraindicated.3 When given for a short period, corticosteroids are safe. For patients with diabetes, monitor glucose levels and be prepared to increase insulin temporarily.

THERAPY FOR CHRONIC GOUT

Urate-lowering therapy is frequently required to control hyperuricemia, and it is essential in advanced stages of gout when patients have evidence of tophi, joint damage, or nephrolithiasis (Table 2).2

Rationale for urate-lowering therapy. Hyperuricemia is defined as a serum urate level of at least 6.8 mg/dL, which is the saturation point for the crystallization of monosodium urate.3 For patients with gout, the goal of urate-lowering therapy is to maintain a serum urate level of 6 mg/dL or lower, to prevent crystal formation and to allow crystal dissolution.4 Evidence shows that reducing serum urate levels and maintaining them at less than 6 mg/dL can positively affect disease outcomes.

In one study, when urate-lowering therapy normalized serum urate levels, crystals disappeared from joints. The number of crystals in synovial fluid samples began to decrease within 3 months of treatment.5

Another study showed that reducing serum urate levels either prevented repeated gout attacks or lowered the frequency of recurrent attacks; 86% of the patients who maintained serum urate levels lower than 6 mg/dL did not have an acute flare during the observation period.6 The lower the serum urate level in response to therapy, the faster the tophi resolve.7

When to initiate long-term therapy. There is little evidencebased information about when to start urate-lowering drugs in the disease course. Discuss this option with the patient after the first attack, and strongly encourage long-term therapy if the patient has had 2 or 3 flares.

If the serum urate level is very high (greater than 10 mg/dL), you may want to start therapy sooner, because disease progression is likely. If the patient has gouty joint changes on radiographs, or if the patient presents with tophi or nephrolithiasis, start urate-lowering therapy immediately.

Wait until the acute attack has fully resolved and the patient has been stable for 1 to 2 weeks before initiating urate-lowering therapy. Individualize the regimen based on the patient’s overall health, comorbidities, and willingness to adhere to long-term treatment. Give anti-inflammatory prophylaxis (discussed below) when urate-lowering therapy is started.

Allopurinol. This potent inhibitor of xanthine oxidase-dehydrogenase is the most commonly used inhibitor of uric acid synthesis. The final step of purine metabolism (and uric acid generation) is catalyzed by xanthine oxidase.8 Allopurinol can be used by those who overproduce uric acid (about 10% of patients with gout) and those who underexcrete it (about 90% of patients). Allopurinol decreases serum urate levels within the first 24 hours after administration. The maximum reduction usually occurs within 2 weeks.

Start allopurinol at 100 mg/d and titrate the dose weekly by 100 mg until the serum urate level drops to less than 6 mg/dL, usually in 1 to 3 weeks. During this period, measure the serum urate level every 2 to 4 weeks. When the patient is stable, urate levels can be monitored once or twice yearly. The standard recommended dosage of allopurinol is 300 mg/d. Some rheumatologists prescribe up to 800 mg/d to reduce the serum urate level to less than 6 mg/dL.

Allopurinol is eliminated by the kidneys; thus, kidney function should be monitored during therapy. If renal impairment is present, lower dosages may be needed (see Table 2). If flares continue to occur, consider dosage escalation, combination medications, or referral.

Adverse effects of allopurinol include rash, GI symptoms, headache, urticaria, and interstitial nephritis.1,9 A hypersensitivity reaction occurs in about 2% of treated patients, usually in those with underlying renal insufficiency or concurrent thiazide use.1,10 Advise patients to call you at the first sign of a rash, which could indicate a more severe hypersensitivity reaction.

Probenecid. Uricosuric agents, such as probenecid, help some patients, but they are rarely prescribed because they are less effective than allopurinol and are more difficult to use. Probenecid acts in the proximal tubule by blocking reabsorption of filtered uric acid.1 Because uricosuric agents work by enhancing uric acid clearance through the kidney, they should be used only in patients with good renal function (creatinine clearance of more than 50 mL/min) who underexcrete uric acid. Before initiating therapy, perform a 24-hour urine uric acid test to identify overproducers. Tell patients that they must drink 8 glasses of water daily, and advise them that aspirin interferes with probenecid. Dosing usually begins at 250 mg bid and can be titrated up to 1 g bid.

Anti-inflammatory prophylaxis with urate-lowering therapy. Although urate-lowering therapy even tually reduces or prevents gouty attacks, initiation of therapy may trigger gouty attacks in the short term because rapid lowering of serum urate leads to mobilization of the urate deposits in cartilage and soft tissue. Prophylaxis with colchicine (0.6 mg qd or bid) or an NSAID (eg, naproxen, 250 mg qd) is usually recommended when urate-lowering therapy is started; it is continued until serum urate levels have been normalized for at least 3 to 6 months.1,11,12

Explain to patients that combination therapy may be necessary for at least 6 months. Encourage them not to discontinue therapy. Prophylaxis for 6 months has been shown to reduce the severity, frequency, and incidence of flares.12 Patients who are taking colchicine long-term should be monitored periodically for axonal neuromyopathy and rhabdomyolysis.

Finally, consider using corticosteroids for anti-inflammatory prophylaxis if colchicine or NSAIDs are contraindicated. Bear in mind, however, that rebound flares may occur when corticosteroids are withdrawn.3

IMPACT OF COMORBIDITIES ON THERAPY

Several other factors complicate the management of gout.13 Patients often have comorbidities, and they may be receiving drugs that create further hurdles to disease management.

Elevated serum urate is associated not only with gout but also with hyperlipidemia, hypertension, diabetes/ insulin resistance, and obesity. Treating these conditions may improve outcomes for patients with gout.4 Keep in mind, though, that some of these treatments (eg, thiazide diuretics for hypertension) increase the risk of gout.

Losartan, an angiotensin II receptor antagonist, is an antihypertensive that has uricosuric activity. Thus, it may lower serum urate in addition to lowering blood pressure, but its clinical role and cost-effectiveness in gout management is not known.4

PATIENT EDUCATION

Encouraging patients to adhere to lifelong therapy is a challenge, particularly when they experience only intermittent symptoms and they may already be taking medications for other conditions. However, adherence may improve if patients receive education about why they need continuous therapy and how intermittent or discontinued therapy can increase attacks and joint damage.

Recommend diet and lifestyle modifications.4 Advise patients to limit their consumption of purinerich foods (red meat and shellfish) and beer.14 Encourage patients who have metabolic syndrome or are overweight to lose weight and avoid soft drinks that have a high fructose content, which is associated with elevated serum urate levels.15 Lifestyle and dietary modification may not be effective in patients with chronic gout; most of them will still need medication to control hyperuricemia. 14,16,17

NEWER THERAPIES

A few investigational compounds offer promising treatment options for gout.

Xanthine oxidase inhibitor. Febuxostat is an investigational, oral, nonpurine selective inhibitor of xanthine oxidase.18 Because it is relatively selective, it may cause fewer adverse effects than allopurinol. Unlike allopurinol, febuxostat is primarily excreted through the liver.10 Therefore, it may be more suitable and effective for patients with mild to moderate renal impairment.18

In a study that compared different doses of febuxostat with placebo, a greater proportion of patients who took the drug achieved serum urate levels of less than 6.0 mg/dL at each visit (P < .001). Most of the participants who received febuxostat attained the targeted serum urate concentration as early as day 7 and maintained it throughout the study period.18

 

Uricolytic agents. PEG-uricase, a less antigenic pegylated form of uricase for parenteral (intravenous) use every 2 to 4 weeks, is currently under review for treatment-resistant gout. Results of the phase 2 and 3 programs showed that it rapidly reduced serum urate concentrations and promoted resorption of tophi.19,20 Pending approval by the FDA, this drug may become a beneficial alternative for patients with treatment-resistant, advanced tophaceous gout.

References:

REFERENCES:


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Therapeutic Agents in This Article


Allopurinol* (Zyloprim)
Aspirin*
Azathioprine* (Imuran)
Colchicine*
Febuxostat†
Heparin*
Indomethacin* (Indocin)
Losartan (Cozaar)
Methylprednisolone* (Medrol)
Naproxen* (Aleve, Anaprox, Naprosyn)
PEG-uricase†
Prednisone*
Probenecid*
Sulindac* (Clinoril)
Warfarin* (Coumadin)
*Available in a generic formulation.
†Investigational compound.