Gout: Uric Acid and Arthritis

• Gout is the most common inflammatory arthritis in the US and western Europe.
• Incidence increases with age, and men are three times more likely to be affected than women due to estrogen's role in uric acid elimination.
• Historically, gout was known as "the disease of kings."

Definitions

• Hyperuricemia: Serum urate (uric acid) level > 6.8 mg/dL.
• Tophi: Aggregate deposits of sodium urate.
• Gout: Recurrent acute arthritis attacks caused by monosodium urate crystal deposits, resulting from elevated serum urate.
  • Primary Gout: No identifiable cause, often associated with obesity, alcohol consumption, hypertension, and hypertriglyceridemia.
  • Secondary Gout: Result of specific drugs, disorders, lead intoxication, or renal failure.

Gout Risk Factors

• Diet: Purine-rich foods (processed meats, fried foods, high sodium content), high fructose corn syrup.
• Demographics and history: Age, male gender, obesity, family history, elevated uric acid.
• Chemotherapy
• Impaired renal function: Up to 70% of gout patients have CKD.
• Conditions: Renal transplantation, hypertension, hyperlipidemia, congestive heart failure.

Drugs That Can Cause Hyperuricemia

• Diuretics: Thiazide, thiazide-like, loop, mineralocorticoid/potassium-sparing (rare).
• Nicotinic acid
• Salicylates: < 2g/day (low dose ASA).
  • Guidelines advise to continue low-dose ASA if patient has gout.
• Ethanol
• Beta-Blockers
• ACE/ARBs: Except losartan.
• Pyrazinamide
• Levodopa
• Ethambutol
• Cyclosporine
• Cytotoxic medications
• Tacrolimus

Pathophysiology

• Purine Metabolism Disorder: The terminal step involves uric acid formation.
• Humans lack uricase, which converts uric acid to water-soluble allantoin.
• Purine Production: Dietary consumption or de novo synthesis.
  • Overproduction: Excessive purine amounts overwhelm excretion mechanisms.
  • Underexcretion: Affects 90% of patients; 2/3 is removed by kidneys, 1/3 by GI bacteria.
• Crystal Deposition: Monosodium urate crystals deposit in joints and cartilage.
  • Uric acid is relatively insoluble; increased levels increase crystallization risk.
  • Deposited crystals trigger an acute inflammatory response.
  • Crystallization Factors: Low temperature favors crystallization in peripheral regions.

Uric Acid Consequences

• Cardiovascular Risk: Uric acid is an emerging risk factor for cardiovascular diseases.
  • Associated conditions: Hypertension, stroke, metabolic disorder, diabetes, kidney disease
  • Increased cardiovascular risk is linked to rising uric acid levels due to societal changes.

Clinical Presentation

• Asymptomatic Hyperuricemia: 10- 15% of patients.
• Acute Gout: Rapid onset, usually at night; intense pain, swelling, erythema, warmth; possible mild fever.
  • Podagra (great toe): Initial attack site in 50% of cases.
  • Untreated attacks last 3-14 days.
• Uncommon clinical presentation
  • More common in the elderly
  • Chronic polyarticular arthritis
  • Multiple small joints in hand, potentially misdiagnosed as rheumatoid arthritis (RA)
• Tophaceous Gout: Urate crystal deposits in soft tissue (cartilage, tendons, synovial membranes).
  • Common locations: Ear helix, wrists, hands, elbows, knees, Achilles tendon, base of great toe.
  • Complications: Pain, tissue/joint damage/deformity, nerve compression syndromes (e.g., carpal tunnel syndrome).

Provocation of Gout

• Triggers: Infection, stress, trauma/surgery, alcohol ingestion, rapid serum lowering by uric acid-lowering agents, medications increasing serum uric acid.

Diagnosis

• Evaluation: Clinical diagnosis (symptoms and physical exam), elevated uric acid, rule out other forms of arthritis, possibly radiographic imaging.
  • Uric Acid Levels: May be normal during an acute attack.
  • Gold Standard: Presence of crystals in synovial fluid analysis.

Treatment Goals

• Immediate Goals: Rapid and effective pain relief to terminate acute attacks.
• Intermediate Goals: Prevention of recurrent attacks.
  • Target serum UA < 6 mg/dL to improve renal outcomes and reduce acute attack risk.
  • Monitor levels post-dose titration.
• Long Term Goals: Prevents complications from chronic urate crystal deposition.
• Overall Goals: Cost-effective therapy while avoiding treatment-related adverse effects.

Nonpharmacologic Treatment

• Acute attacks: Joint rest (1-2 days), ice application.
• Medications: Eliminate non-essential prescriptions causing hyperuricemia. It is conditionally recommended to switch hydrochlorothiazide.
• Hydration: Drink greater than 2L water daily.
• Weight Loss: Recommended in obese/overweight patients.
• Diet Changes: Limit high-fructose corn syrup, purine intake, and alcohol.
  • Men ≤ 2 drinks/day; Women ≤ 1 drink/day.
  • Guidelines conditionally advise against vitamin C supplementation.

Treatment Types

• Used for acute attacks: NSAIDs, corticosteroids, colchicine, IL-1 inhibitors.
  • Opioids are not recommended.
• Used for preventative treatment: Xanthine Oxidase Inhibitors (XOI), Uricosurics, and Pegylated Recombinant Uricase Enzyme.

Acute Gouty Arthritis Treatment

• Monotherapy: Recommended for mild-moderate attacks in few small joints or one large joint.
• Combination Therapy: Recommended for severe pain, especially with multiple small joints or >1 large joint.

Chronic Management of Gout

• Used when 1 flare but infrequent flares, serum urate > 9 mg/dL.
• Not Indicated For:
  • Asymptomatic hyperuricemia, even with CKD, urolithiasis, or radiographic changes.
  • First “uncomplicated” flare.
  • Long-term use, not treating the acute flare.
• Can be started during a flare, and continued during flares.
• Initiate anti-inflammatory therapy during ULT initiation.

Three mechanisms to decrease uric acid

• Decrease synthesis: Xanthine Oxidase Inhibitors (XOI): allopurinol, febuxostat.
• Increase renal excretion: Uricosurics: probenecid.
  • Drugs with uricosuric properties: fenofibrate, losartan, SGLT-2 inhibitors.
• Enzymatically degrade: Pegloticase.

American College of Rheumatology (ACR) Recommendations

• First-Line Agent: Allopurinol is the preferred first-line agent.
  • Start with a low dose and titrate to reduce flare risk.
    • Allopurinol: 50-100 mg daily.
    • Febuxostat: 40 mg daily.
    • Probenecid: 500 mg once-twice daily.
• Lower doses recommended for CKD Stage 3 or worse.
• Duration: ULT is recommended indefinitely.
• Initiation: Can start ULT during a gout flare if therapy is indicated.
• Switching Agents: Switch to a second XOI over adding a uricosuric for persistently high SUA despite maximized dose, frequent flares or unresolved tophi.
• Last-Line Treatment: Pegloticase.

Xanthine Oxidase Inhibitors

• First-line agents for decreasing uric acid.
• Recommended over probenecid for patients with CKD Stage 3 or worse.
• Allopurinol preferred due to cost and cardiovascular safety versus febuxostat.
• Efficacy: Similar rates in gout flares and reaching goal UA level.

Allopurinol [Zyloprim®, Aloprim®]

• MOA: Blocks xanthine oxidase enzyme to decrease UA production.
• Active metabolite, oxypurinol, inhibits xanthine oxidase; renally cleared.
• Dose: Initiate at 50-100 mg once daily and titrate every 2-5 weeks to UA < 6 mg/dL.
  • Peak effect at 1 week after initiation.
  • Doses > 300 mg should be divided for GI tolerability.
  • Max dose: 800 mg/day.
  • Reduce dose in renal impairment.
  • Most patients not titrated to appropriate dose.
• Adverse Effects:
  • Mild: Headache, GI problems, urticaria, skin rash, increased AST/ALT.
  • Serious: Dose-dependent Stevens Johnson Syndrome(SJS)/Toxic Epidermal Necrolysis(TEN), interstitial nephritis, hepatitis.
• Drug Interactions:
  • Thiazides decrease excretion.
  • Dose reduction for azathioprine.
• Allopurinol Hypersensitivity Syndrome (AHS):
  • Occurs in 1:1000 in the US; 20-25% mortality.
  • Symptoms: SJS/TEN, eosinophilia, vasculitis, rash, end-organ damage.
• Pharmacogenetic Testing (HLA-b*5801):
  • High-risk populations: Asian (Korean with Stage 3+ CKD, Han Chinese, Thai) and Black populations.
  • Recommended testing prior to therapy in high-risk groups.
  • Greatest predictor of AHS is initial starting dose; start low, go slow!
  • Desensitization: Guidelines conditionally recommend if other oral ULT agents are not suitable.

Febuxostat [Uloric®]

• Role in Therapy:
  • Use: May be useful in patients with allopurinol hypersensitivity/intolerance.
  • Switch: Guidelines suggest switching patients to alternative oral ULT with CVD history/new CVD-related event.
• MOA: Non-purine selective XOI.
  • Inhibits oxidized and reduced forms of xanthine oxidase.
• Dose: 40 mg once daily; increase to 80 mg daily after 2 weeks if UA > 6 mg/dL; can increase to 120 mg if clinically needed.
  • No dosage adjustments for mild-moderate renal disease.
• Adverse Effects: Diarrhea, rash, nausea, blood dyscrasias, arthritis, eosinophilia.
  • Liver enzyme elevations: Requires LFT monitoring: baseline, 2 months, 4 months.
• Excretion: Equal excretion into urine and feces after liver metabolism.
• Contraindications: Azathioprine, mercaptopurine.
• Precautions: High rate of cardiovascular events compared to allopurinol: MI, stroke, heart-related death.
• FDA Safety Alert:
  • CARES study found febuxostat non-inferior to allopurinol for CV adverse events.
  • All-cause and CV mortality higher in febuxostat group.
  • Serum UA lowering may be less effective in patients with higher previous allopurinol dose, renal impairment, male gender.

Uricosurics

• Increases renal excretion of uric acid.
• Role in Therapy: May be useful as an add-on to XOI if XOI alone doesn't reach UA goal.
  • Best for underexcretors, but guidelines don't recommend 24-hour urine before starting.
• Probenecid:
  • MOA: Increases renal excretion by decreasing renal tubular reabsorption.
  • Kidney Stones: May cause kidney stone formation (9-11%).
    • Maintain adequate urine flow and alkalization.
  • Dose: 250 mg BID for 1 week; may increase to 500 mg BID.
    • Start at low dose and titrate.
    • Max dose: 2 g/day.
  • Contraindications: Avoid use if CrCl < 30 mL/min.