Pharmacology of Drugs for Gout

Introduction/Overview

Gout is a common inflammatory arthritis characterized by the deposition of monosodium urate crystals in joints and other tissues, resulting from chronic hyperuricemia. The condition manifests as recurrent, intensely painful acute attacks and, if untreated, can progress to chronic tophaceous gout with joint destruction and renal impairment. The pharmacological management of gout is a cornerstone of rheumatological practice and represents a classic example of targeted therapy based on a clear understanding of pathophysiology. Effective treatment requires a dual approach: managing the acute inflammatory flare and providing long-term urate-lowering therapy to prevent recurrence and complications. The drugs used in gout have distinct and often complementary mechanisms, ranging from anti-inflammatory agents to inhibitors of uric acid synthesis and enhancers of its excretion. A thorough grasp of their pharmacology is essential for rational therapeutic decision-making, which must be tailored to the phase of the disease, patient comorbidities, and pharmacokinetic profiles.

Learning Objectives

• Classify the pharmacological agents used in the treatment of acute gout attacks and chronic hyperuricemia based on their primary mechanism of action.
• Explain the molecular and cellular mechanisms by which colchicine, NSAIDs, corticosteroids, xanthine oxidase inhibitors, and uricosuric agents exert their therapeutic effects in gout.
• Analyze the pharmacokinetic properties of major anti-gout drugs, including absorption, distribution, metabolism, and excretion, and relate these to dosing regimens and considerations in special populations.
• Evaluate the major adverse effect profiles, contraindications, and significant drug interactions associated with each class of anti-gout medication.
• Formulate appropriate pharmacological strategies for the acute management of gout flares and the long-term prophylaxis of hyperuricemia, integrating patient-specific factors such as renal function and comorbidities.

Classification

Anti-gout drugs are systematically classified based on their therapeutic intent and primary pharmacological target. This classification reflects the dual therapeutic strategy inherent in gout management.

Drugs for Acute Gout Attacks

These agents are employed for the rapid suppression of inflammation and pain during an acute flare. Their use is typically short-term.

• Nonsteroidal Anti-inflammatory Drugs (NSAIDs): Non-selective COX inhibitors (e.g., indomethacin, naproxen) and selective COX-2 inhibitors (e.g., celecoxib).
• Colchicine: A unique anti-inflammatory agent derived from the autumn crocus (Colchicum autumnale).
• Corticosteroids: Systemic oral (e.g., prednisone) and intra-articular (e.g., triamcinolone acetonide) formulations.
• Interleukin-1 (IL-1) Inhibitors: Biologic agents (e.g., anakinra, canakinumab) used in refractory or contraindicated cases.

Drugs for Chronic Hyperuricemia (Urate-Lowering Therapy, ULT)

These agents are used for long-term management to lower serum urate levels below the saturation point (typically <6 mg/dL or <5 mg/dL in severe disease) to prevent crystal formation and dissolve existing deposits.

• Xanthine Oxidase Inhibitors:
  • Purine analogues: Allopurinol and its active metabolite oxypurinol.
  • Non-purine analogues: Febuxostat.
• Uricosuric Agents: Enhance renal excretion of uric acid.
  • First-generation: Probenecid.
  • Second-generation: Lesinurad.
• Uricolytic Agents: Enzymes that catalyze the oxidation of uric acid to allantoin.
  • Pegloticase (a pegylated recombinant uricase).

Mechanism of Action

The pharmacodynamic actions of anti-gout drugs are directed at distinct points in the inflammatory cascade triggered by monosodium urate crystals or in the metabolic pathway of uric acid synthesis and elimination.

Mechanisms in Acute Gout Management

The acute gout flare is an innate immune response to deposited crystals. Phagocytosis of crystals by synovial macrophages activates the NLRP3 inflammasome, leading to caspase-1 activation and the cleavage of pro-IL-1β into active IL-1β. This potent pyrogen initiates a robust inflammatory cascade involving neutrophil recruitment, cytokine release, and complement activation.

Colchicine

Colchicine binds with high affinity to soluble tubulin, forming a colchicine-tubulin complex. This complex binds to the ends of microtubules, preventing their polymerization and elongation. The disruption of microtubule dynamics inhibits several critical cellular functions in neutrophils and other motile cells: chemotaxis (directed migration towards the inflammatory site), phagocytosis of urate crystals, and the release of preformed inflammatory mediators from granules. Furthermore, microtubule inhibition may impair the assembly and function of the NLRP3 inflammasome, thereby reducing IL-1β production. Its effect is predominantly prophylactic against inflammation rather than curative of established inflammation.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

NSAIDs exert their anti-inflammatory, analgesic, and antipyretic effects through the inhibition of cyclooxygenase (COX) enzymes. COX catalyzes the conversion of arachidonic acid to prostaglandin H₂, the precursor for prostanoids including prostaglandin E₂ (PGE₂). PGE₂ is a key mediator of pain, vasodilation, and increased vascular permeability in inflammation. Non-selective NSAIDs (e.g., indomethacin, naproxen) inhibit both COX-1 and COX-2 isoforms. COX-2 selective inhibitors (coxibs, e.g., celecoxib) primarily target the inducible COX-2 enzyme expressed at sites of inflammation, offering a potentially improved gastrointestinal safety profile but with cardiovascular considerations.

Corticosteroids

Glucocorticoids like prednisone act via intracellular glucocorticoid receptors. The ligand-receptor complex translocates to the nucleus, where it modulates gene transcription. This leads to the increased synthesis of anti-inflammatory proteins (e.g., lipocortin-1, which inhibits phospholipase A₂) and the decreased transcription of genes encoding pro-inflammatory cytokines (e.g., IL-1β, TNF-α, IL-6), adhesion molecules, and COX-2. The net effect is a broad suppression of the inflammatory and immune response at multiple levels.

Interleukin-1 Inhibitors

These biologic agents directly target the IL-1 pathway. Anakinra is a recombinant form of the endogenous IL-1 receptor antagonist (IL-1Ra), which competitively inhibits the binding of IL-1α and IL-1β to the IL-1 type I receptor. Canakinumab is a human monoclonal antibody that selectively binds to and neutralizes IL-1β. By blocking IL-1 signaling, these drugs interrupt the central cytokine cascade responsible for the symptoms of an acute gout flare.

Mechanisms in Urate-Lowering Therapy

Xanthine Oxidase Inhibitors

These agents target the enzyme responsible for the final steps of uric acid production. Xanthine oxidase catalyzes two reactions: the oxidation of hypoxanthine to xanthine and the oxidation of xanthine to uric acid. Allopurinol, a purine analogue, is a substrate for xanthine oxidase and is metabolized to oxypurinol (alloxanthine). Both allopurinol and oxypurinol are competitive inhibitors of xanthine oxidase, with oxypurinol providing the long-lasting activity due to its prolonged tissue binding and slow clearance. Febuxostat is a non-purine, selective inhibitor of xanthine oxidase that binds reversibly to the molybdenum-pterin center of the enzyme. By inhibiting xanthine oxidase, these drugs reduce the production of uric acid from its purine precursors, thereby lowering serum urate concentrations.

Uricosuric Agents

Uricosurics work at the level of renal tubular transport. Uric acid is freely filtered at the glomerulus but undergoes extensive reabsorption (≈90%) and secretion in the proximal tubule. The major reabsorptive transporters are URAT1 (urate anion transporter 1) and GLUT9. Probenecid and lesinurad inhibit URAT1, thereby blocking the reabsorption of uric acid and promoting its net renal excretion. Lesinurad may also inhibit other organic anion transporters involved in reabsorption (OAT4, OAT10). It is important to note that uricosurics lose efficacy in the setting of significant renal impairment (e.g., creatinine clearance <30 mL/min).

Uricolytic Agent: Pegloticase

Pegloticase is a pegylated recombinant mammalian uricase (urate oxidase). Humans lack a functional uricase enzyme due to evolutionary mutations. Uricase catalyzes the oxidation of relatively insoluble uric acid into highly soluble allantoin, which is readily excreted by the kidneys. Pegloticase provides this missing enzymatic activity, resulting in a rapid and profound reduction in serum urate levels. The pegylation extends the drug’s circulating half-life and may modestly reduce immunogenicity.

Pharmacokinetics

The pharmacokinetic profiles of anti-gout drugs significantly influence their dosing schedules, therapeutic utility, and safety in patients with organ dysfunction.

Colchicine

Colchicine is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations (C_max) occurring within 0.5 to 2 hours. Oral bioavailability is variable but approximately 45%. It undergoes extensive enterhepatic recirculation and distributes widely, concentrating in leukocytes, which may explain its prolonged anti-inflammatory effect despite a short plasma half-life (t_1/2) of about 9 hours in healthy adults. Colchicine is primarily metabolized by the cytochrome P450 3A4 (CYP3A4) isoenzyme and is a substrate for the efflux transporter P-glycoprotein (P-gp). The majority of the drug and its metabolites are excreted in feces via biliary elimination, with about 10-20% excreted unchanged in urine. Dose reduction is imperative in patients with renal or hepatic impairment and in those taking strong CYP3A4 or P-gp inhibitors, due to the risk of severe toxicity.

Nonsteroidal Anti-inflammatory Drugs

Pharmacokinetics vary widely among NSAIDs. Most are well absorbed orally, are highly protein-bound (>90%, primarily to albumin), and have small volumes of distribution. They are primarily metabolized in the liver via oxidation and conjugation (e.g., CYP2C9 for many). Elimination is mostly renal, either as metabolites or unchanged drug (e.g., ketorolac). Half-lives range from short (2-4 hours for ibuprofen) to long (≥20 hours for piroxicam, celecoxib). The selectivity of COX-2 inhibitors does not alter their fundamental pharmacokinetic parameters but influences their adverse effect profile.

Corticosteroids

Oral corticosteroids like prednisone are well absorbed. Prednisone is a prodrug that is converted to its active form, prednisolone, in the liver. Prednisolone is approximately 90% protein-bound (to transcortin and albumin) and has a plasma half-life of 2-4 hours, although its biological effect persists much longer due to genomic mechanisms. Metabolism occurs primarily in the liver via reduction and conjugation, followed by renal excretion of metabolites. Dosing adjustments may be necessary in hepatic disease, which can impair the prednisone to prednisolone conversion.

Allopurinol

Allopurinol is approximately 90% absorbed from the gut. Its C_max occurs 1-2 hours post-dose. Allopurinol itself has a short half-life (1-2 hours) and is rapidly oxidized by xanthine oxidase to its active metabolite, oxypurinol. Oxypurinol is eliminated renally, largely unchanged, with a half-life of approximately 18-30 hours in patients with normal renal function. This long half-life permits once-daily dosing. Oxypurinol clearance is directly proportional to creatinine clearance; therefore, its half-life increases dramatically in renal impairment, necessitating dose reduction to prevent accumulation and toxicity. Allopurinol and oxypurinol are not significantly protein-bound.

Febuxostat

Febuxostat is well absorbed (≥85%) and reaches C_max in 1-1.5 hours. It is extensively metabolized in the liver via conjugation (UGT enzymes: UGT1A1, UGT1A3, UGT1A9) and oxidation (CYP isoenzymes play a minor role). The metabolites are pharmacologically inactive. Febuxostat is eliminated via both renal (≈50%) and fecal (≈45%) routes. Its elimination half-life is approximately 5-8 hours. Importantly, febuxostat pharmacokinetics are not significantly altered in patients with mild to moderate renal or hepatic impairment, offering an advantage over allopurinol in some patients with kidney disease. No dose adjustment is typically required.

Probenecid

Probenecid is completely absorbed orally. It is highly protein-bound (85-95%) and has a half-life of 4-12 hours, dose-dependent due to saturation of hepatic metabolism. It is metabolized in the liver to active glucuronide and hydroxylated metabolites, which are also uricosuric. Excretion is primarily renal, with significant tubular secretion. Its uricosuric effect is dose-dependent and can be overcome by high tubular fluid uric acid concentrations, highlighting the importance of adequate hydration and dose titration.

Pegloticase

Pegloticase is administered as an intravenous infusion every two weeks. Its pharmacokinetics are characterized by a two-compartment model. The pegylation confers a longer terminal half-life (≈14 days) compared to non-pegylated uricase. Clearance is mediated by both peptidase metabolism and immune-mediated clearance. The development of anti-drug antibodies, which occurs in a significant proportion of patients, can increase clearance, reduce efficacy, and increase the risk of infusion reactions. Serum urate levels must be monitored before each infusion to detect this immunogenicity.

Therapeutic Uses/Clinical Applications

The application of anti-gout drugs is strictly guided by the clinical phase of the disease: acute management versus long-term prophylaxis.

Acute Gout Flare Management

Treatment should be initiated within the first 24 hours of symptom onset for optimal efficacy. Monotherapy is often sufficient, but combination therapy (e.g., NSAID with colchicine) may be used for severe flares.

• NSAIDs: First-line agents for patients without contraindications (e.g., renal disease, peptic ulcer, heart failure). A full anti-inflammatory dose is used for 5-10 days, often with a taper. Indomethacin has historical use but no proven superiority over other NSAIDs like naproxen.
• Colchicine: Most effective if given within 12-24 hours of flare onset. A low-dose regimen (1.2 mg initially, followed by 0.6 mg one hour later, then 0.6 mg once or twice daily) is now standard to minimize gastrointestinal toxicity. It is particularly useful when NSAIDs or corticosteroids are contraindicated.
• Corticosteroids: First-line for patients with polyarticular flares, renal impairment, or contraindications to NSAIDs/colchicine. Oral prednisone (0.5 mg/kg/day for 5-10 days, then tapered) is common. Intra-articular steroids are highly effective for monoarticular flares.
• IL-1 Inhibitors: Reserved for patients with frequent flares who are refractory to or have contraindications for all first-line therapies. They provide rapid relief but are costly.

Urate-Lowering Therapy (ULT) for Chronic Management

ULT is indicated for patients with frequent acute flares (≥2 per year), tophaceous gout, chronic gouty arthritis, or renal stones. Critically, ULT should not be initiated during an acute flare due to the risk of prolonging or exacerbating the attack. Prophylaxis against flares (with low-dose colchicine or an NSAID) is mandatory when starting any ULT and should be continued for at least 3-6 months.

• Allopurinol: First-line ULT for most patients. Dosing is initiated low (100 mg daily or lower in renal impairment) and titrated upwards every 2-5 weeks based on serum urate response, with a typical maximum dose of 300 mg daily, though doses up to 800 mg daily may be used under specialist supervision. The target serum urate is <6 mg/dL (<5 mg/dL for severe disease).
• Febuxostat: First-line alternative to allopurinol, particularly in patients with mild-to-moderate renal impairment. Starting dose is 40 mg daily, increased to 80 mg daily if target serum urate is not achieved after 2 weeks. A cardiovascular risk warning exists based on the CARES trial findings.
• Probenecid: Used as second-line ULT in patients with preserved renal function (CrCl >50 mL/min) who are under-excretors of uric acid. It is less effective in renal impairment. Starting dose is 250 mg twice daily, titrated to a maximum of 2 g daily. Concomitant use with a xanthine oxidase inhibitor can be synergistic.
• Pegloticase: Reserved for severe, treatment-refractory gout in patients who have failed or are intolerant to conventional ULT. It is highly effective at reducing tophi and achieving target urate levels but is associated with significant cost, infusion reactions, and immunogenicity. Pre-treatment with antihistamines and corticosteroids is standard to mitigate infusion reactions.

Adverse Effects

The adverse effect profiles of anti-gout drugs are diverse and can be severe, necessitating careful patient selection and monitoring.

Colchicine

Dose-dependent toxicity is a major concern. Gastrointestinal effects (nausea, vomiting, diarrhea, abdominal pain) are the most common and often the earliest signs of toxicity. Myotoxicity (rhabdomyolysis) and neurotoxicity (peripheral neuropathy, myopathy) can occur, especially with chronic use or in the setting of drug interactions or organ impairment. Bone marrow suppression (leukopenia, thrombocytopenia, aplastic anemia) is a rare but serious effect. Overdose can cause multi-organ failure, disseminated intravascular coagulation, and death. There is no specific antidote; treatment is supportive.

Nonsteroidal Anti-inflammatory Drugs

Adverse effects are related to COX-1 inhibition (gastrointestinal, renal) and COX-2 inhibition (cardiovascular). Common effects include dyspepsia, gastroduodenal ulceration, and bleeding. Renal effects include reduced glomerular filtration rate, sodium and water retention, hyperkalemia, and interstitial nephritis. All NSAIDs carry an increased risk of cardiovascular thrombotic events (myocardial infarction, stroke). Non-selective NSAIDs may also inhibit platelet aggregation. Hypersensitivity reactions, including bronchospasm in aspirin-sensitive asthmatics, can occur.

Corticosteroids

Short-term use for acute gout is generally well-tolerated but can cause hyperglycemia, fluid retention, hypertension, mood disturbances, and insomnia. The risks of long-term use (osteoporosis, avascular necrosis, Cushing’s syndrome, adrenal suppression, increased infection risk) are not typically relevant to acute gout management.

Xanthine Oxidase Inhibitors

• Allopurinol: The most feared adverse effect is the allopurinol hypersensitivity syndrome (AHS), a rare but potentially fatal reaction characterized by rash (which may progress to Stevens-Johnson syndrome or toxic epidermal necrolysis), fever, eosinophilia, hepatitis, and acute renal failure. Risk is higher in patients of Han Chinese or Thai descent with the HLA-B*5801 allele, in those with renal impairment on inappropriately high doses, and during concomitant thiazide diuretic use. Other common effects include maculopapular rash, gastrointestinal upset, and drowsiness.
• Febuxostat: Common adverse effects include liver function test abnormalities, nausea, and arthralgias. A black box warning exists for an increased risk of cardiovascular death compared to allopurinol, based on post-marketing trial data. Liver function monitoring is recommended.

Uricosuric Agents

Probenecid is generally well-tolerated. Gastrointestinal upset and rash are most common. A significant risk is the precipitation of acute uric acid nephropathy or nephrolithiasis due to increased urinary uric acid excretion; this is mitigated by initiating therapy at a low dose, gradual titration, and maintaining high fluid intake (≥2 L/day) and alkalinization of urine (pH 6-6.5). Probenecid is contraindicated in patients with a history of uric acid kidney stones. Headache and dizziness may also occur.

Pegloticase

The most significant adverse effects are infusion reactions (flushing, urticaria, dyspnea, chest pain, hypotension) and anaphylaxis, which are more common in patients who develop high titers of anti-drug antibodies. Other effects include gout flares (especially during initial months of therapy), nausea, ecchymosis, and constipation. A black box warning exists for the risk of anaphylaxis and infusion reactions. Contraindications include glucose-6-phosphate dehydrogenase (G6PD) deficiency due to the risk of hemolysis and methemoglobinemia from hydrogen peroxide generated during uric acid oxidation.

Drug Interactions

Significant drug interactions are common with anti-gout medications and must be carefully managed.

Colchicine

Colchicine is involved in critical pharmacokinetic interactions. Strong inhibitors of CYP3A4 (e.g., clarithromycin, ketoconazole, ritonavir) and P-glycoprotein (e.g., cyclosporine) can dramatically increase colchicine plasma levels, leading to severe toxicity. These combinations are often contraindicated or require substantial dose reduction. Concurrent use with other myotoxic drugs (e.g., statins, fibrates) may increase the risk of rhabdomyolysis.

Nonsteroidal Anti-inflammatory Drugs

NSAIDs can interact with numerous drug classes. They may reduce the antihypertensive effect of ACE inhibitors, angiotensin II receptor blockers, and diuretics. They increase the risk of bleeding with anticoagulants (warfarin, DOACs) and antiplatelets. Concurrent use with corticosteroids or SSRIs increases the risk of GI bleeding. NSAIDs can increase lithium and methotrexate levels by reducing renal clearance. They may also antagonize the diuretic effect of furosemide and thiazides.

Allopurinol

The interaction with azathioprine and 6-mercaptopurine is life-threatening. Allopurinol inhibits xanthine oxidase, which is also the primary enzyme responsible for the metabolism of these thiopurine immunosuppressants. Coadministration leads to profound accumulation of active metabolites, causing severe bone marrow suppression. The dose of azathioprine/6-MP must be reduced by approximately 75% if allopurinol is essential. Allopurinol may also potentiate the myelosuppressive effects of cyclophosphamide and increase the risk of rash when combined with ampicillin or amoxicillin.

Probenecid

Probenecid was originally developed to prolong penicillin levels by inhibiting their renal tubular secretion. It similarly increases plasma concentrations of many other drugs excreted by anion transport, including methotrexate (risk of severe toxicity), NSAIDs, acyclovir, and zidovudine. Salicylates (aspirin) at low doses (<2 g/day) antagonize the uricosuric effect of probenecid and should be avoided.

Febuxostat and Pegloticase

Febuxostat has fewer clinically significant pharmacokinetic interactions. It is a weak inhibitor of CYP2D6 and CYP1A2. Pegloticase interactions are not extensively characterized but are primarily pharmacodynamic; for instance, other ULTs are typically discontinued prior to initiation to allow monitoring of the drug’s effect via serum urate levels.

Special Considerations

Pregnancy and Lactation

Most anti-gout drugs should be used with extreme caution or are contraindicated during pregnancy and breastfeeding. Colchicine crosses the placenta and may be associated with fetal harm; its use is generally restricted to life-threatening familial Mediterranean fever. NSAIDs should be avoided in the third trimester due to risks of premature ductus arteriosus closure and oligohydramnios. Corticosteroids may be used if necessary, but high doses or prolonged use can cause fetal adrenal suppression. Allopurinol is classified as Category C; it may be used for severe maternal hyperuricemia (e.g., preeclampsia with hyperuricemia) but not for routine gout. Febuxostat, probenecid, and pegloticase are not recommended. Consultation with a maternal-fetal medicine specialist is essential.

Pediatric and Geriatric Considerations

Gout is rare in children, usually secondary to inborn errors of metabolism (e.g., Lesch-Nyhan syndrome) or malignancy. Allopurinol is the mainstay, with dosing based on weight and careful monitoring. In geriatric patients, age-related declines in renal and hepatic function, polypharmacy, and comorbidity prevalence necessitate caution. Lower starting doses and slower titration are paramount for colchicine, allopurinol, and NSAIDs. NSAID use is particularly hazardous in the elderly due to increased risks of GI bleeding, renal failure, and heart failure exacerbation.

Renal Impairment

Renal function is a critical determinant in anti-gout drug selection and dosing.

• Colchicine: Dose must be reduced. Severe renal impairment (CrCl <30 mL/min) contraindicates the use of colchicine with strong CYP3A4/P-gp inhibitors.
• NSAIDs: Generally contraindicated in moderate-to-severe renal impairment (CrCl <30 mL/min) due to the risk of further reducing glomerular filtration rate and causing acute kidney injury.
• Allopurinol: Dose must be reduced according to creatinine clearance. Oxypurinol accumulation can lead to toxicity. The recommended starting dose is 50 mg daily in CrCl 10-20 mL/min and 50 mg every other day in CrCl 3-10 mL/min.
• Febuxostat: No dose adjustment is required for mild-to-moderate renal impairment (CrCl 30-89 mL/min). It is often preferred over allopurinol in this population. Use with caution in severe impairment (CrCl <30 mL/min).
• Probenecid: Ineffective in CrCl <50 mL/min and is contraindicated.
• Pegloticase: Can be used in renal impairment, but patients with end-stage renal disease were excluded from clinical trials.

Hepatic Impairment

Dose reduction of colchicine is required in hepatic impairment due to reduced metabolism. NSAIDs should be used cautiously, as they can cause hepatotoxicity. Allopurinol can cause hepatitis as part of AHS. Febuxostat is metabolized in the liver; while no formal dose adjustment is recommended for mild impairment, caution is advised in moderate-to-severe hepatic impairment. The safety of pegloticase in significant hepatic disease is not established.

Summary/Key Points

• Gout pharmacology is bifurcated into agents for acute inflammatory flares (NSAIDs, colchicine, corticosteroids) and agents for long-term urate-lowering therapy (xanthine oxidase inhibitors, uricosurics, uricase).
• Colchicine’s unique mechanism involves microtubule disruption, inhibiting neutrophil chemotaxis and inflammasome activity. Its narrow therapeutic index mandates careful dosing, especially with renal/hepatic impairment or interacting drugs.
• Xanthine oxidase inhibitors (allopurinol, febuxostat) are first-line ULT. Allopurinol requires renal dose adjustment and carries a risk of hypersensitivity syndrome; febuxostat may be preferable in renal impairment but has a cardiovascular risk warning.
• Uricosurics (probenecid) increase renal uric acid excretion but are ineffective in renal impairment and require hydration to prevent nephrolithiasis.
• Pegloticase, a recombinant uricase, is reserved for refractory gout and produces a profound urate-lowering effect but is associated with significant immunogenicity and infusion reaction risks.
• Initiation of any ULT must be accompanied by anti-inflammatory flare prophylaxis (e.g., low-dose colchicine) for at least 3-6 months and should not be started during an acute attack.
• Patient-specific factors—particularly renal function, comorbidities (CVD, GI disease), concomitant medications, and HLA-B*5801 status—are paramount in selecting and dosing anti-gout therapy.

Clinical Pearls

• For an acute gout flare, “start early and choose wisely” based on patient comorbidities. A low-dose colchicine regimen is as effective and far safer than the historical high-dose regimen.
• When starting allopurinol, “start low and go slow.” Begin at 100 mg daily (or lower in renal impairment) and titrate upwards every 2-5 weeks until the serum urate target (<6 mg/dL) is achieved. This minimizes flare risk and possibly the risk of hypersensitivity.
• Serum urate levels should be monitored periodically (e.g., every 2-5 weeks during dose titration, then every 6 months once stable) to ensure target levels are maintained.
• In patients of Han Chinese or Thai descent, consider HLA-B*5801 screening prior to allopurinol initiation to identify those at high risk for severe cutaneous adverse reactions.
• Pegloticase therapy requires pre-infusion serum urate monitoring. A rise in serum urate above 6 mg/dL, particularly to pre-treatment levels, indicates the development of anti-drug antibodies and loss of efficacy, necessitating discontinuation.

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