What are the latest treatment guidelines for hyperuricemia?

Latest Treatment Guidelines for Hyperuricemia

Xanthine oxidase inhibitors (allopurinol or febuxostat) are the first-line pharmacologic treatment for hyperuricemia in gout, with a target serum urate level below 6 mg/dL for all patients, and below 5 mg/dL for those with severe disease including tophi. 1, 2

Initial Assessment and Screening

• Perform a thorough clinical evaluation including history and physical examination to assess for symptoms of arthritis, presence of tophi, and signs of acute or chronic synovitis 2, 3, 4
• Screen for secondary causes of hyperuricemia including comorbidities (obesity, hypertension, diabetes, hyperlipidemia) and medications that elevate uric acid (thiazides, loop diuretics, niacin, calcineurin inhibitors) 2, 3, 4
• Consider 24-hour urine uric acid evaluation for patients with gout onset before age 25 or history of urolithiasis to identify uric acid overproduction 2, 3, 4
• Measure creatinine clearance accurately, not just serum creatinine, as this impacts drug selection and dosing decisions 1

Lifestyle and Dietary Modifications

Diet and lifestyle measures alone provide only 10-18% reduction in serum urate and are insufficient as monotherapy for most patients with sustained hyperuricemia above 7 mg/dL. 1, 4

Dietary Recommendations to Limit:

• Purine-rich meats and seafood 1, 2, 3
• High fructose corn syrup sweetened soft drinks and energy drinks 1, 2, 3
• Alcohol consumption, particularly beer, but also wine and spirits 1, 2

Dietary Recommendations to Encourage:

• Low-fat or non-fat dairy products 1, 2, 4
• Weight reduction if obese 1

Complete Alcohol Abstinence:

• Required during periods of active gout arthritis, especially with inadequate medical control 1

Pharmacologic Treatment Algorithm

First-Line Therapy: Xanthine Oxidase Inhibitors

Start with allopurinol 100 mg daily and titrate upward every 2-5 weeks by 100 mg increments until target serum urate is achieved, without exceeding 800 mg daily. 2, 3, 5

• Allopurinol is recommended as the initial XOI for most patients 1, 2, 3
• Febuxostat is an appropriate alternative XOI with equivalent efficacy, particularly when allopurinol is contraindicated or not tolerated 1, 2, 3
• The 2012 ACR guidelines do not preferentially recommend one XOI over the other, though the 2016 EULAR guidelines recommend allopurinol first based on cost-effectiveness considerations 1

Dosing Considerations for Allopurinol:

• Mild gout: 200-300 mg/day 5
• Moderately severe tophaceous gout: 400-600 mg/day 5
• Maximum recommended dose: 800 mg/day 5
• Renal impairment (CrCl 10-20 mL/min): 200 mg/day 5
• Renal impairment (CrCl <10 mL/min): Maximum 100 mg/day 5
• Extreme renal impairment (CrCl <3 mL/min): May need to lengthen interval between doses 5

Alternative First-Line Therapy: Uricosuric Agents

• Probenecid is recommended as an alternative first-line option when XOIs are contraindicated or not tolerated 1, 2, 3, 6
• Probenecid should NOT be used as first-line monotherapy in patients with creatinine clearance below 50 mL/min 1

Combination Therapy for Refractory Disease

When serum urate target is not achieved with XOI monotherapy, combination therapy with one XOI (allopurinol or febuxostat) plus one uricosuric agent (probenecid, fenofibrate, or losartan) is recommended. 1

Third-Line Therapy: Pegloticase

• Pegloticase is reserved exclusively for severe gout with refractory disease that has failed maximum appropriate doses of oral XOI and uricosuric combination therapy 1, 2, 3, 4
• Pegloticase is NOT recommended as first-line therapy for any clinical scenario 1

Target Serum Urate Levels

• Minimum target for all gout patients: <6 mg/dL 1, 2, 3, 4
• Target for patients with greater disease severity (tophi, chronic tophaceous gout): <5 mg/dL 1, 2, 3, 4
• Avoid long-term therapy targeting serum uric acid <3 mg/dL 4
• The upper limit of normal is approximately 7 mg/dL for men and postmenopausal women, and 6 mg/dL for premenopausal women 5

Monitoring Protocol

• Monitor serum urate every 2-5 weeks during urate-lowering therapy (ULT) titration 1, 2, 3, 4
• Continue monitoring every 6 months once target is achieved to assess adherence 1, 2, 3, 4
• Normal serum urate levels are typically achieved within 1-3 weeks of appropriate dosing 5

Special Clinical Scenarios

Chronic Kidney Disease (CKD)

• Gout with CKD stage 2-5 or end-stage renal disease is an appropriate indication for pharmacologic ULT by itself in patients with prior gout attacks and current hyperuricemia 1, 4
• XOIs are preferred over uricosuric agents in CKD patients 1
• Febuxostat lacks published safety data for stage 4 or worse CKD 1
• Dose adjustment of allopurinol is mandatory based on creatinine clearance 5

Initiating ULT During Acute Gout Attack

• The ACR recommends that pharmacologic ULT can be started during an acute gout attack if effective anti-inflammatory management has been instituted 1
• The EULAR guidelines do not recommend this approach 1

Tumor Lysis Syndrome

• For hyperuricemia associated with tumor lysis syndrome, rasburicase is recommended for rapid uric acid reduction 3, 4
• For prevention of uric acid nephropathy during vigorous neoplastic disease therapy, allopurinol 600-800 mg daily for 2-3 days with high fluid intake is recommended 5

Critical Pitfalls and Caveats

Common Treatment Failures:

• Failure to titrate allopurinol adequately: Many patients require doses above 300 mg daily to achieve target serum urate, yet underdosing is extremely common 1, 2
• Poor medication adherence: This is a pervasive problem in gout management, making regular serum urate monitoring essential 1, 2, 4
• Starting at excessively high doses: Always use a "start low, go slow" approach to minimize acute flare risk and improve adherence 1
• Neglecting flare prophylaxis: Continue anti-inflammatory therapy (colchicine or NSAIDs) during ULT initiation until serum urate is normalized and the patient has been free of acute attacks for several months 5

Medication Transitions:

• When transferring from a uricosuric agent to allopurinol, gradually reduce the uricosuric dose over several weeks while gradually increasing allopurinol 5
• Allopurinol is better tolerated when taken following meals 5

Fluid Management:

• Maintain fluid intake sufficient to yield daily urinary output of at least 2 liters 5
• Maintain neutral or slightly alkaline urine pH 5

HLA-B*5801 Screening:

• Consider HLA-B*5801 screening in high-risk populations before initiating allopurinol due to increased risk of severe cutaneous adverse reactions (SCARs) 1, 4
• The risk is particularly elevated in patients with renal failure where oxypurinol accumulates 1