What is the next best step for a patient with gout who has not responded to allopurinol (xanthine oxidase inhibitor) 300mg and febuxostat (xanthine oxidase inhibitor), with no decrease in uric acid levels?

Management of Refractory Hyperuricemia After Failed Xanthine Oxidase Inhibitor Therapy

First: Verify Adequate Dosing and Adherence

Before considering treatment failure, confirm that both xanthine oxidase inhibitors were titrated to maximum effective doses, as most patients require doses above commonly prescribed levels to achieve target serum uric acid <6 mg/dL. 1

• Allopurinol: Maximum FDA-approved dose is 800 mg/day, yet most patients receive only 300 mg/day despite requiring higher doses for efficacy 1
• Febuxostat: Maximum FDA-approved dose in the US is 80 mg/day (120 mg/day available outside the US), with the 80 mg dose achieving target serum uric acid <6 mg/dL in 67% of patients compared to only 42% with allopurinol 300 mg 2, 3
• Verify medication adherence through patient interview and pharmacy records, as non-adherence is a common cause of apparent treatment failure 4

Next Step: Add a Uricosuric Agent

If both xanthine oxidase inhibitors were appropriately dosed to maximum levels and the patient has adequate renal function (eGFR >50 mL/min), add probenecid as combination therapy rather than switching agents. 2, 5

• Probenecid can be added to febuxostat at 500 mg once or twice daily, then titrated upward to achieve target serum uric acid <6 mg/dL 1, 2
• This combination addresses hyperuricemia through dual mechanisms: reduced uric acid production (xanthine oxidase inhibition) plus increased renal excretion (uricosuric effect) 2
• Critical contraindication: Do not use uricosuric agents if eGFR <50 mL/min, history of kidney stones, or moderate-to-severe CKD 1, 5

If Combination Therapy Fails: Consider Pegloticase

For severe refractory gout with persistent hyperuricemia despite maximally dosed oral urate-lowering therapy, pegloticase (intravenous uricase) is indicated, particularly if tophi are present or quality of life is significantly impaired. 2, 6

Pegloticase Protocol:

• Administered as 8 mg IV infusion every 2 weeks over at least 120 minutes in a healthcare setting equipped to manage anaphylaxis 6
• Mandatory pre-treatment: Antihistamines and corticosteroids before each infusion to reduce anaphylaxis risk (6.5% incidence) 6
• Critical monitoring: Check serum uric acid before each infusion; discontinue if levels rise above 6 mg/dL on two consecutive measurements, as this indicates antibody formation and dramatically increased anaphylaxis risk 6
• Must discontinue all oral urate-lowering therapy before starting pegloticase, as concomitant use may mask treatment failure by blunting serum uric acid rise 6
• Screen for G6PD deficiency before initiation (absolute contraindication due to hemolysis risk), particularly in patients of African or Mediterranean ancestry 6

Mandatory Flare Prophylaxis Throughout Treatment Changes

Initiate or continue anti-inflammatory prophylaxis with colchicine 0.5-1 mg daily (or low-dose NSAIDs if colchicine contraindicated) for at least 6 months when adding uricosuric therapy or switching to pegloticase. 1, 2, 6

• Any change in urate-lowering strategy mobilizes urate crystals from tissue deposits, triggering acute flares 6
• Prophylaxis should continue for 3-6 months minimum, with ongoing evaluation and extension if flares persist 1

Common Pitfalls to Avoid

• Underdosing xanthine oxidase inhibitors: Most patients require allopurinol >300 mg/day or febuxostat 80 mg/day to reach target, yet many clinicians stop at lower doses 1, 2
• Premature switching: Switching between xanthine oxidase inhibitors without maximizing the first agent's dose wastes time, as both work through the same mechanism 4
• Combining allopurinol and febuxostat: Never use both simultaneously—this provides no additional benefit and doubles adverse effect exposure 4
• Omitting flare prophylaxis: Failure to provide anti-inflammatory prophylaxis during treatment intensification is a major cause of patient non-adherence and perceived treatment failure 4
• Using uricosurics in renal impairment: Probenecid and other uricosurics are ineffective and potentially harmful when eGFR <50 mL/min 1, 5

Target Serum Uric Acid Level

• Standard target: <6 mg/dL for all patients with gout, maintained lifelong 2, 4
• Aggressive target: <5 mg/dL for patients with severe disease burden (tophi, chronic arthropathy, frequent attacks) to facilitate faster crystal dissolution 2
• Monitor serum uric acid every 2-5 weeks during dose titration, then every 6 months once target achieved 1, 5