What type of enzyme is pegloticase (pegylated uricase)?

Answers to Gout Management Questions

Question 1: Pegloticase Mechanism of Action

Pegloticase is a pegylated uricase (Answer C). 1, 2

• Pegloticase is a recombinant modified mammalian urate oxidase (uricase) produced by a genetically modified strain of Escherichia coli, covalently conjugated to monomethoxypoly(ethylene glycol). 2
• It functions by enzymatically catalyzing the oxidation of uric acid into allantoin, a more water-soluble end product that is readily excreted by the kidneys. 1, 3
• This mechanism is fundamentally different from xanthine oxidase inhibitors (which block uric acid production) or uricosuric agents (which increase renal excretion of uric acid). 3, 4

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Question 2: Initiating ULT During Gout Flare Resolution

Start ULT together with anti-inflammatory prophylaxis (Answer C). 5

• The American College of Rheumatology strongly recommends concomitant anti-inflammatory prophylaxis therapy for at least 3–6 months when initiating urate-lowering therapy to prevent flares. 5
• The European League Against Rheumatism recommends colchicine as the preferred prophylactic option when starting ULT. 5
• A "start low, go slow" approach with gradual dose titration is recommended, as this results in fewer episodes of acute gout during treatment initiation and improves ULT adherence. 1
• Common pitfall: Initiating ULT without prophylaxis commonly leads to gout flares, which can undermine patient adherence and treatment success. 5

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Question 3: Cardiometabolic Medication That Lowers Urate

Sodium-glucose cotransporter-2 inhibitors (Answer C).

While the provided evidence does not specifically address SGLT2 inhibitors' uricosuric effects, the European League Against Rheumatism guidelines note that certain medications used for cardiovascular comorbidities can have uricosuric properties. 1 The guidelines emphasize assessing and managing cardiovascular risk factors in all gout patients. 5

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Question 4: Xanthine Oxidase Inhibitor

Febuxostat (Answer C). 1

• Febuxostat is a xanthine oxidase inhibitor that has been found more effective in patients with chronic kidney disease than allopurinol given at doses adjusted to creatinine clearance. 1
• Allopurinol is also a xanthine oxidase inhibitor and remains the American College of Rheumatology's recommended first-line ULT. 5
• Important distinction: Probenecid is a uricosuric agent, pegloticase is a pegylated uricase, and anakinra is an IL-1 receptor antagonist used for acute flares. 1

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Question 5: MSU Crystal Birefringence

Strongly negative birefringence (Answer D).

Monosodium urate crystals demonstrate strongly negative birefringence under compensated polarized light microscopy, which is the gold standard diagnostic feature distinguishing gout from other crystal arthropathies like calcium pyrophosphate deposition disease (which shows positive birefringence). 5

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Question 6: Radiographic Features of Tophaceous Gout

Well-defined erosions with sclerotic margins and overhanging bony edges (Answer C).

Advanced tophaceous gout characteristically produces erosions with overhanging edges (also called "overhanging edge sign" or "rat-bite erosions") on plain radiography, which distinguishes it from other erosive arthropathies. This finding reflects the destructive nature of tophaceous deposits on bone.

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Question 7: Advanced Imaging for MSU Crystal Detection

Dual-energy computed tomography (DECT) (Answer D).

DECT can identify the specific presence of monosodium urate crystals based on their chemical composition, providing a non-invasive alternative to joint aspiration when crystal identification is needed but aspiration is not feasible or has been non-diagnostic.

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Clinical Context: Pegloticase as Pegylated Uricase

Pegloticase represents a fundamentally different therapeutic approach to severe refractory gout by enzymatically degrading uric acid rather than blocking its production or enhancing its excretion. 1, 3

Indications and Patient Selection

• Pegloticase is reserved exclusively for patients with crystal-proven severe debilitating chronic tophaceous gout and poor quality of life, in whom the serum uric acid target cannot be reached with any other available drug at maximal dosage (including combinations of xanthine oxidase inhibitors and uricosuric agents). 1, 6, 2
• It is not recommended as first-line ULT for any gout scenario. 1, 6
• The American College of Rheumatology specifies that pegloticase is appropriate for patients with severe gout disease burden and refractoriness to, or intolerance of, conventional and appropriately dosed ULT. 1

Efficacy Profile

• In phase III trials, pegloticase achieved serum uric acid levels <6 mg/dL in 42% of patients on average, compared to 0% in the placebo group. 1
• Pegloticase profoundly lowers serum urate, resolves tophi, reduces tender and swollen joint counts, decreases pain, and improves patients' global assessments and quality of life. 3, 4

Critical Safety Considerations

• Allergic reactions occur in approximately 25%–30% of patients receiving pegloticase biweekly. 1
• The major limitation is immunogenicity and the emergence of anti-drug antibodies that result in increased drug clearance, loss of efficacy, and infusion reactions. 3, 7
• Pegloticase should not be combined with other urate-lowering therapies as this may mask increases in serum uric acid levels that warn of increased risk of infusion reactions and anaphylaxis. 6
• Pharmacologic oral ULT agents should be discontinued during pegloticase therapy to avoid masking the loss of pegloticase serum urate lowering effect associated with increased risk of infusion reactions. 1
• Approximately 90% of patients develop anti-pegloticase antibodies, and about 10% experience serious adverse effects including infusion reactions, anaphylaxis, and skin infections. 8, 9

Treatment Duration and Monitoring

• There is no firm consensus on the appropriate duration of pegloticase therapy. 1, 6
• The European League Against Rheumatism suggests considering a switch to oral ULT once all tophi have disappeared, if feasible. 1, 6
• Critical monitoring strategy: Pegloticase should be stopped when there is a loss of serum urate lowering, as this indicates antibody formation and predicts infusion reactions. 3, 7