Pharmacology of Drugs for Gout

Introduction/Overview

Gout represents a common and complex form of inflammatory arthritis characterized by the deposition of monosodium urate crystals in joints and other tissues, resulting from chronic hyperuricemia. The condition manifests through acute, intensely painful attacks, chronic arthropathy, and the potential development of tophi. The pharmacological management of gout is multifaceted, targeting both the acute inflammatory episodes and the underlying metabolic disorder of uric acid homeostasis. Effective treatment necessitates a clear understanding of the distinct pathophysiological phases: acute gouty inflammation and long-term urate-lowering therapy for chronic hyperuricemia. The clinical relevance of this therapeutic area is underscored by the rising global prevalence of gout, its association with comorbidities such as hypertension, chronic kidney disease, and metabolic syndrome, and the significant burden of disease related to pain, disability, and reduced quality of life.

Learning Objectives

• Classify the pharmacological agents used in gout management according to their therapeutic intent: acute attack treatment versus chronic urate-lowering therapy.
• Explain the molecular and cellular mechanisms of action for anti-inflammatory agents (e.g., colchicine, NSAIDs, corticosteroids) and urate-lowering drugs (e.g., xanthine oxidase inhibitors, uricosurics, uricases).
• Analyze the pharmacokinetic profiles of key gout medications, including considerations for absorption, metabolism, excretion, and dosing adjustments in special populations.
• Evaluate the major adverse effect profiles, contraindications, and significant drug-drug interactions associated with each class of gout medication.
• Formulate appropriate therapeutic strategies for acute gout attacks and long-term management of hyperuricemia, incorporating patient-specific factors such as renal function and comorbidity profiles.

Classification

Drugs for gout are primarily classified based on their therapeutic purpose in managing the disease’s different phases. This functional classification provides a clinically useful framework for selection and use.

Drugs for Acute Gout Attacks

These agents aim to rapidly terminate the inflammatory response triggered by urate crystals. They do not lower serum urate levels but are crucial for symptomatic relief during flares.

• Colchicine: An alkaloid derived from the plant Colchicum autumnale.
• Nonsteroidal Anti-inflammatory Drugs (NSAIDs): Non-selective COX inhibitors (e.g., naproxen, indomethacin) and selective COX-2 inhibitors (e.g., celecoxib).
• Corticosteroids: Systemic (e.g., oral prednisone, intramuscular triamcinolone) and intra-articular formulations.
• Interleukin-1 (IL-1) Inhibitors: Biologic agents such as anakinra, canakinumab, and rilonacept, typically reserved for refractory cases or patients with contraindications to first-line therapies.

Drugs for Chronic Management and Urate-Lowering Therapy (ULT)

These agents are used for long-term management to reduce serum urate levels, prevent acute attacks, and promote dissolution of existing crystals and tophi.

• Xanthine Oxidase Inhibitors:
  • Purine Analogues: Allopurinol and its active metabolite oxypurinol.
  • Non-purine Analogues: Febuxostat.
• Uricosuric Agents: Increase renal excretion of uric acid.
  • First-Generation: Probenecid.
  • Second-Generation: Lesinurad.
• Uricase Enzymes (Recombinant): Catalyze the oxidation of uric acid to allantoin.
  • Pegloticase (pegylated recombinant uricase).

Mechanism of Action

Drugs for Acute Gout: Anti-inflammatory Mechanisms

The acute gout flare is an innate immune response to monosodium urate crystals, involving neutrophil recruitment, phagocytosis, and the release of pro-inflammatory cytokines.

Colchicine

Colchicine binds specifically and reversibly to tubulin, the protein subunit of microtubules. This binding inhibits microtubule polymerization, leading to the disruption of the cytoskeleton in neutrophils and other motile cells. The primary anti-inflammatory effects in gout are mediated through several downstream consequences: inhibition of neutrophil chemotaxis and adhesion to the endothelium; impairment of phagocytosis of urate crystals; and suppression of the assembly of the NLRP3 inflammasome, a multiprotein complex that activates caspase-1. Caspase-1 is required for the cleavage and secretion of active interleukin-1β (IL-1β), a pivotal cytokine in gouty inflammation. By inhibiting inflammasome activation, colchicine reduces IL-1β production and subsequent inflammatory cascade amplification.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

NSAIDs exert their therapeutic effect primarily through the inhibition of cyclooxygenase (COX) enzymes, which catalyze the conversion of arachidonic acid to prostaglandins and thromboxanes. In the context of acute gout, non-selective NSAIDs (inhibiting both COX-1 and COX-2) and selective COX-2 inhibitors reduce the synthesis of prostaglandin E₂ (PGE₂) at the site of inflammation. PGE₂ is a potent mediator of vasodilation, pain sensitization, and fever. The reduction in prostaglandin levels attenuates the cardinal signs of inflammation: redness, swelling, heat, and pain. The anti-inflammatory potency varies among agents, with indomethacin and naproxen historically being commonly selected for gout flares.

Corticosteroids

Corticosteroids, such as prednisone, act via genomic and non-genomic mechanisms. The primary effect involves diffusion across the cell membrane and binding to cytosolic 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 mediators, including cytokines (IL-1, IL-6, TNF-α), chemokines, adhesion molecules, and COX-2. The net result is a broad suppression of the inflammatory response, including reduced neutrophil migration and decreased production of multiple inflammatory cytokines central to the gout flare.

Drugs for Chronic Management: Urate-Lowering Mechanisms

Xanthine Oxidase Inhibitors

These agents target the enzyme responsible for uric acid production. Xanthine oxidase catalyzes the final two steps in purine catabolism: the oxidation of hypoxanthine to xanthine and xanthine to uric acid. Allopurinol, a purine analogue, is a substrate for xanthine oxidase and is metabolized to oxypurinol (alloxanthine). Both allopurinol and oxypurinol act as competitive inhibitors of the enzyme, with oxypurinol providing a long-lasting non-competitive inhibition due to its tight binding and slow dissociation from the reduced form of the enzyme. Febuxostat, a non-purine selective inhibitor, binds reversibly to the molybdenum-pterin center of xanthine oxidase in both its oxidized and reduced forms. By inhibiting xanthine oxidase, these drugs decrease the conversion of purine precursors to uric acid, thereby reducing serum and urinary uric acid concentrations.

Uricosuric Agents

Uricosurics lower serum uric acid by enhancing its renal excretion. Uric acid handling in the kidney involves filtration, nearly complete reabsorption, subsequent secretion, and post-secretory reabsorption. The major transporters involved are URAT1 (urate anion transporter 1), which mediates reabsorption, and GLUT9 (glucose transporter 9). Probenecid and lesinurad act primarily by inhibiting URAT1 on the apical membrane of proximal tubular cells, thereby blocking the reabsorption of uric acid from the tubular lumen back into the blood. This inhibition increases the net renal excretion of uric acid. Lesinurad may also exhibit weak inhibition of another organic anion transporter, OAT4. These agents are generally less effective in patients with significant renal impairment, as their action depends on adequate glomerular filtration.

Uricase Enzymes

Uricase (urate oxidase) is an enzyme not present in humans due to evolutionary gene silencing. It catalyzes the oxidation of relatively insoluble uric acid to highly soluble allantoin, which is readily excreted by the kidneys. Pegloticase is a recombinant mammalian uricase conjugated with methoxy polyethylene glycol (PEG). The PEGylation prolongs the circulating half-life and reduces immunogenicity, though anti-drug antibodies remain a significant concern. By rapidly and profoundly lowering plasma uric acid concentrations, pegloticase promotes the dissolution of tophi and is effective in patients refractory to or intolerant of oral urate-lowering therapies.

Pharmacokinetics

Colchicine

Colchicine is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations (C_max) achieved within 0.5 to 2 hours. Oral bioavailability is variable but approximately 45%. It undergoes significant enterolepatic recirculation. Distribution is widespread, with high concentrations in leukocytes, which may contribute to its therapeutic effect. Colchicine is metabolized primarily by the cytochrome P450 3A4 (CYP3A4) isoenzyme in the liver, and its metabolites are excreted in feces and urine. The elimination half-life (t_1/2) in patients with normal renal and hepatic function is approximately 27 to 31 hours. Dosing must be adjusted in renal and hepatic impairment, and concomitant use of potent CYP3A4 or P-glycoprotein inhibitors is contraindicated due to the risk of severe, potentially fatal toxicity.

Nonsteroidal Anti-inflammatory Drugs

Pharmacokinetic properties vary considerably among NSAIDs. Most are well absorbed orally, highly protein-bound (>90%), and have volumes of distribution that approximate plasma volume. They are metabolized extensively in the liver via cytochrome P450 pathways (primarily CYP2C9) and glucuronidation. Renal excretion of unchanged drug or metabolites is the primary route of elimination. Half-lives range from short (e.g., ibuprofen, t_1/2 ≈ 2 hours) to long (e.g., piroxicam, t_1/2 ≈ 50 hours). For acute gout, NSAIDs with a relatively rapid onset and intermediate half-life, such as naproxen (t_1/2 ≈ 14 hours), are often preferred to allow for convenient twice-daily dosing during the short treatment course.

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 converted 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. The clearance of oxypurinol is directly proportional to creatinine clearance; therefore, dose reduction is mandatory in renal impairment to prevent accumulation and toxicity. Allopurinol and oxypurinol are minimally protein-bound.

Febuxostat

Febuxostat is well absorbed (>80%) and reaches C_max in 1-1.5 hours. It is extensively metabolized in the liver via conjugation by uridine diphosphate glucuronosyltransferases (UGT) and oxidation by CYP isoenzymes (CYP1A2, 2C8, 2C9, and non-CYP pathways). The metabolites are excreted in both urine (≈30%) and feces (≈50%). The elimination half-life is approximately 5-8 hours. Unlike allopurinol, febuxostat metabolism is primarily hepatic, and no dose adjustment is required for mild to moderate renal impairment. However, caution is advised in severe renal impairment, and it is not recommended in patients with severe hepatic impairment.

Probenecid

Probenecid is completely absorbed orally, with a C_max at 2-4 hours. It is highly protein-bound (85-95%) and has a volume of distribution of approximately 0.15 L/kg. Probenecid is metabolized in the liver, producing active glucuronide and hydroxylated metabolites. Both the parent drug and metabolites are excreted in the urine. The plasma half-life is dose-dependent, ranging from 6 to 12 hours. Renal excretion is enhanced in alkaline urine. Its efficacy is markedly reduced when creatinine clearance falls below 50 mL/min.

Pegloticase

Pegloticase is administered as an intravenous infusion every two weeks. Its pharmacokinetics are not characterized by traditional absorption and distribution models due to its biologic nature. The PEGylation increases its molecular size, prolonging its circulation time and reducing renal clearance. The mean terminal half-life is approximately 14 days. The development of high-titer anti-pegloticase antibodies accelerates clearance, leading to a loss of the urate-lowering response and an increased risk of infusion reactions. Therapeutic drug monitoring typically involves serial measurement of serum uric acid levels rather than plasma drug concentrations.

Therapeutic Uses/Clinical Applications

Management of Acute Gout Flares

Treatment should be initiated within the first 24 hours of symptom onset for optimal efficacy. The choice of agent depends on the number of joints involved, severity of symptoms, and patient comorbidities.

• Colchicine: Most effective when given within 12-24 hours of flare onset. A low-dose regimen (e.g., 1.2 mg initially, followed by 0.6 mg one hour later, then 0.6 mg once or twice daily) is now standard, as it provides similar efficacy with markedly reduced gastrointestinal toxicity compared to historical high-dose regimens.
• NSAIDs: A first-line option for patients without contraindications (e.g., renal disease, peptic ulcer disease, heart failure, anticoagulant use). Full anti-inflammatory doses are used for 5-10 days, often with a taper.
• Corticosteroids: Preferred for patients with polyarticular flares, renal impairment, or contraindications to colchicine and NSAIDs. Oral prednisone (e.g., 30-40 mg daily for 5 days) or a single intramuscular dose can be effective. Intra-articular steroids are highly effective for monoarticular flares, especially in large, accessible joints.
• IL-1 Inhibitors: Reserved for patients with frequent flares who are refractory to or have contraindications for all the above therapies.

Urate-Lowering Therapy (ULT) for Chronic Management

ULT is indicated for patients with frequent acute attacks (≥2 per year), chronic gouty arthritis, tophi, or radiographic damage. A treat-to-target strategy is employed, with a serum urate goal of <6 mg/dL (<360 μmol/L), or <5 mg/dL (<300 μmol/L) for those with severe disease.

• Xanthine Oxidase Inhibitors (Allopurinol, Febuxostat): First-line agents for most patients. Therapy is initiated at a low dose (allopurinol 100 mg daily, febuxostat 40 mg daily) and titrated upward every 2-5 weeks based on serum urate monitoring until the target is reached. Allopurinol dosing can exceed 300 mg daily, even in renal impairment, with appropriate monitoring, contrary to outdated guidelines.
• Uricosurics (Probenecid, Lesinurad): Used as an alternative first-line in patients with underexcretion of uric acid (24-hour urinary uric acid <800 mg on a general diet) and normal renal function, or as add-on therapy with a xanthine oxidase inhibitor for patients not reaching target on monotherapy. Lesinurad is only approved for use in combination with a xanthine oxidase inhibitor.
• Pegloticase: Indicated for the treatment of chronic gout in adult patients refractory to conventional ULT, or for whom these therapies are contraindicated. It is reserved for severe, debilitating tophaceous gout due to its cost, route of administration, and risk profile.

Prophylaxis During Initiation of ULT

A critical clinical application is the use of anti-inflammatory prophylaxis to prevent the acute flares commonly triggered by the rapid change in serum urate levels when ULT is started. Low-dose colchicine (0.5-0.6 mg once or twice daily) is the preferred agent and is typically continued for at least 6 months. If colchicine is contraindicated, a low-dose NSAID or prednisone may be used. Prophylaxis should be continued until the patient has been free of flares for several months and the serum urate is stable at target.

Adverse Effects

Colchicine

Adverse effects are dose-dependent and more common with high-dose regimens. Gastrointestinal effects (nausea, vomiting, diarrhea, abdominal pain) are the most frequent and often limit therapy. Myotoxicity (rhabdomyolysis) and neurotoxicity (peripheral neuropathy, myopathy) can occur, particularly with long-term use or in the setting of renal/hepatic impairment or drug interactions. Bone marrow suppression (leukopenia, thrombocytopenia, aplastic anemia) is a rare but serious complication. Overdose can cause multi-organ failure, disseminated intravascular coagulation, and death.

NSAIDs

Adverse effects are related to COX-1 inhibition (gastrointestinal, renal) and COX-2 inhibition (cardiovascular). Common effects include dyspepsia, gastritis, and peptic ulcer disease. Renal effects include reduced glomerular filtration rate, fluid retention, hypertension, and hyperkalemia. All NSAIDs carry an increased risk of cardiovascular thrombotic events (myocardial infarction, stroke). Non-selective NSAIDs also impair platelet aggregation via thromboxane inhibition, increasing bleeding risk.

Corticosteroids

Short-term use for acute gout is generally well-tolerated but can cause hyperglycemia, mood changes, insomnia, and fluid retention. Long-term use, which is not typical for gout management, is associated with a wide array of serious effects: Cushing’s syndrome, osteoporosis, avascular necrosis, immunosuppression, cataracts, and adrenal suppression.

Allopurinol

The most common adverse effects are rash and gastrointestinal upset. The most serious is allopurinol hypersensitivity syndrome (AHS), a rare but potentially fatal reaction characterized by severe rash (Stevens-Johnson syndrome, toxic epidermal necrolysis), fever, hepatitis, eosinophilia, and progressive renal failure. The risk of AHS is higher in patients of Han Chinese or Thai descent with the HLA-B*5801 allele, in those with renal impairment, and with inappropriate high initial dosing. Other effects include leukopenia, thrombocytopenia, and, rarely, vasculitis.

Febuxostat

Common adverse effects include liver function test abnormalities, nausea, and arthralgias. A significant concern identified in a large post-marketing trial (CARES) was a potentially increased risk of cardiovascular death compared to allopurinol, leading to a Boxed Warning in the United States. It is thus contraindicated in patients with established ischemic heart disease or congestive heart failure. As with all ULT, it increases the risk of acute gout flares during initiation.

Uricosuric Agents

Probenecid is generally well-tolerated but can cause gastrointestinal distress, rash, and headache. A major concern is the increased risk of urolithiasis due to increased urinary uric acid excretion; this risk is mitigated by adequate hydration, urine alkalinization, and avoiding use in patients with a history of stones. Lesinurad carries risks of renal-related adverse events, including serum creatinine elevation and, rarely, acute kidney injury, particularly if used without adequate hydration or as monotherapy without a xanthine oxidase inhibitor.

Pegloticase

The most significant adverse effects are related to immunogenicity. Infusion reactions (flushing, urticaria, dyspnea, chest pain, hypotension) occur in a substantial minority of patients and are more common in those with high anti-drug antibody titers. Premedication with antihistamines and corticosteroids is standard. A Boxed Warning exists for the risk of anaphylaxis. Another major risk is the paradoxical increase in gout flares during the initial months of therapy. Furthermore, the loss of the urate-lowering effect due to antibody development necessitates regular monitoring of serum urate levels before each infusion; a level above 6 mg/dL on two consecutive occasions indicates treatment failure and mandates discontinuation to avoid the high risk of infusion reactions.

Drug Interactions

Colchicine

Colchicine is a substrate for both CYP3A4 and the efflux transporter P-glycoprotein (P-gp). Concomitant use with strong inhibitors of either system can dramatically increase colchicine plasma concentrations, leading to severe toxicity. Such interactions are contraindicated in patients with renal or hepatic impairment and require dose reduction or avoidance in others. Key interacting drugs include:

• Strong CYP3A4/P-gp Inhibitors: Clarithromycin, erythromycin, ketoconazole, itraconazole, cyclosporine, ritonavir, verapamil, diltiazem.
• Statins and Fibrates: Increased risk of myotoxicity and rhabdomyolysis when combined with colchicine.

Allopurinol

• Azathioprine/6-Mercaptopurine: Allopurinol inhibits xanthine oxidase, which is also the primary route of metabolism for these immunosuppressants. Coadministration leads to profound, potentially fatal accumulation of azathioprine/6-MP, resulting in severe bone marrow suppression. The dose of azathioprine/6-MP must be reduced by approximately 75% if allopurinol is essential, with close monitoring.
• Amoxicillin/Ampicillin: An increased incidence of rash is observed when these antibiotics are given with allopurinol.
• Warfarin: Case reports suggest allopurinol may potentiate the anticoagulant effect, necessitating closer INR monitoring.
• Diuretics (especially thiazides): May increase serum urate levels, potentially antagonizing the effect of allopurinol and increasing the risk of AHS.

Febuxostat

Febuxostat is metabolized by multiple UGT and CYP enzymes. It does not appear to be a strong inducer or inhibitor of major CYP enzymes. However, it may increase the plasma concentrations of theophylline (a CYP1A2 substrate) and desipramine (a CYP2D6 substrate). Caution is advised when co-administering with azathioprine or 6-mercaptopurine, though the interaction is considered less predictable than with allopurinol.

Probenecid

Probenecid was originally developed to prolong the action of penicillin by inhibiting its renal tubular secretion. It affects the renal excretion of numerous drugs:

• Inhibits Excretion: Methotrexate, NSAIDs, loop and thiazide diuretics, cephalosporins, acyclovir, zidovudine, and many others. This can lead to increased plasma levels and toxicity of these agents.
• Salicylates (e.g., aspirin): Doses above 325 mg daily inhibit the uricosuric effect of probenecid, rendering it ineffective for gout. Low-dose aspirin (<325 mg) does not appear to have this effect.

Pegloticase

Formal drug interaction studies have not been conducted. However, due to the risk of infusion reactions and anaphylaxis, it may be prudent to avoid initiating other new medications, particularly those with a high risk of allergic reactions, around the time of infusion.

Special Considerations

Pregnancy and Lactation

Most gout medications pose potential risks during pregnancy and lactation. Colchicine crosses the placenta and is excreted in breast milk. While low-dose use may be considered in certain circumstances (e.g., familial Mediterranean fever), its use for gout in pregnancy is generally avoided due to theoretical risks of fetal harm. NSAIDs are contraindicated in the third trimester due to risks of premature closure of the ductus arteriosus and oligohydramnios. Allopurinol is classified as Pregnancy Category C; it may be used if clearly needed, but chronic use is typically deferred. Febuxostat, probenecid, lesinurad, and pegloticase have insufficient human data and are not recommended. Acute gout in pregnancy is often managed with corticosteroids, which are preferred over other options, though the lowest effective dose for the shortest duration should be used.

Pediatric Considerations

Gout is rare in children, usually secondary to inborn errors of metabolism (e.g., Lesch-Nyhan syndrome) or malignancy. Allopurinol is the most commonly used ULT in pediatric populations, with dosing based on body weight or surface area. Colchicine can be used for acute flares or prophylaxis, with careful dose adjustment. Safety and efficacy data for febuxostat, lesinurad, and pegloticase in children are limited.

Geriatric Considerations

Elderly patients often have age-related declines in renal and hepatic function, multiple comorbidities, and polypharmacy, necessitating careful drug selection and dosing. Renal function should be assessed via estimated glomerular filtration rate (eGFR), not serum creatinine alone. Lower starting doses of colchicine, allopurinol, and NSAIDs are imperative. NSAIDs should be used with extreme caution, if at all, due to high risks of gastrointestinal bleeding, renal impairment, and cardiovascular events. Febuxostat may be considered in patients with renal impairment, but its cardiovascular risk profile requires careful evaluation.

Renal Impairment

Renal function is a critical determinant in gout therapy.

• Colchicine: Dose reduction is required. Severe renal impairment (eGFR <30 mL/min) contraindicates use with strong CYP3A4/P-gp inhibitors. In dialysis patients, a maximum dose of 0.6 mg every 2-3 days is often recommended.
• NSAIDs: Generally contraindicated in moderate to severe renal impairment due to the risk of further reducing glomerular filtration and causing acute kidney injury.
• Allopurinol: Oxypurinol clearance is reduced. Dosing should be based on eGFR, starting low (e.g., 50-100 mg daily) and titrating upward with monitoring. The old “creatinine clearance-based” maximum dose cap is no longer recommended; doses above 300 mg can be used with careful monitoring to achieve serum urate target.
• Febuxostat: No dose adjustment is needed for mild to moderate renal impairment (eGFR ≥30). Use with caution in severe impairment.
• Uricosurics: Generally ineffective when eGFR is <50 mL/min and are not recommended.
• Pegloticase: Can be used in renal impairment, including end-stage renal disease, as its action is independent of renal function.

Hepatic Impairment

Patients with hepatic impairment require caution.

• Colchicine: Contraindicated in severe hepatic impairment due to reduced metabolism and increased risk of toxicity.
• NSAIDs: Should be used cautiously due to increased risk of gastrointestinal bleeding and potential for hepatotoxicity.
• Allopurinol: Use with caution; severe hepatic disease is a risk factor for allopurinol hypersensitivity syndrome.
• Febuxostat: Not recommended in severe hepatic impairment (Child-Pugh Class C).
• Uricosurics and Pegloticase: No specific dose adjustments for hepatic impairment, but general caution is advised.

Summary/Key Points

• Gout pharmacology is dichotomized into acute anti-inflammatory therapy (colchicine, NSAIDs, corticosteroids) and chronic urate-lowering therapy (xanthine oxidase inhibitors, uricosurics, uricase).
• Colchicine acts by inhibiting microtubule polymerization, disrupting neutrophil function and NLRP3 inflammasome activation. Its use is limited by gastrointestinal toxicity and dangerous interactions with CYP3A4/P-gp inhibitors.
• Xanthine oxidase inhibitors (allopurinol, febuxostat) are first-line for ULT. Allopurinol requires renal dose adjustment and carries a risk of hypersensitivity syndrome, while febuxostat carries a boxed warning for potential cardiovascular risk.
• Initiation of any ULT frequently precipitates acute flares, mandating concurrent anti-inflammatory prophylaxis (typically low-dose colchicine) for at least 6 months.
• Pegloticase is a potent intravenous option for refractory gout but is associated with significant risks of immunogenicity, infusion reactions, and anaphylaxis, requiring careful patient selection and monitoring.
• Drug selection must be highly individualized, incorporating patient-specific factors: renal and hepatic function, cardiovascular risk profile, comedications, and comorbidities.
• The therapeutic goal of ULT is a serum urate level <6 mg/dL (<360 μmol/L), with a lower target for those with tophi, to achieve crystal dissolution and prevent long-term joint damage.

Clinical Pearls

• For acute gout, start treatment early and choose based on comorbidity: NSAIDs for the healthy, colchicine (low-dose) for many, steroids for those with renal issues or on anticoagulants.
• When starting allopurinol, “start low and go slow”: begin at 100 mg daily (lower if renal impaired) and titrate upwards every 2-5 weeks based on serum urate levels, not symptoms.
• Always prescribe prophylaxis against flares when initiating ULT. Failure to do so is a common reason for patient non-adherence.
• In a patient on allopurinol who develops a rash, discontinue the drug immediately and evaluate for signs of allopurinol hypersensitivity syndrome.
• Before administering pegloticase, check a serum urate level. If it is >6 mg/dL, investigate for the development of anti-drug antibodies, as continued infusion carries a high risk of severe reaction.

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