Gout and Hyperuricemia PDF

Gout and Hyperuricemia Dermatology/Musculoskeletal ZACHARY HEETER, PHARMD, BCPS,BCGP 1 Learning Objectives ◦ List recommended therapies for acute gout flares ◦ List recommended therapies for prevention of acute gout flares ◦ Determine which situations warr...

Gout and Hyperuricemia Dermatology/Musculoskeletal ZACHARY HEETER, PHARMD, BCPS,BCGP 1 Learning Objectives ◦ List recommended therapies for acute gout flares ◦ List recommended therapies for prevention of acute gout flares ◦ Determine which situations warrant the addition of treatment to prevent gout flares ◦ List the goal serum urate concentration when using urate lowering therapy ◦ State the place in therapy for pegloticase ◦ Given a patient case, recommend appropriate treatment for acute gout flare and urate lowering therapy ◦ Recommend appropriate monitoring for urate lowering therapy and therapy for acute gout flare 2 Gout Inflammatory response to precipitation of monosodium urate (MSU) crystals in tissue Underlying metabolic disorder is elevated serum uric acid level (hyperuricemia) ◦ Defined as serum supersaturated with MSU that it begins to exceed the limit of solubility ◦ Approximately above 6.8 mg/dL Hyperuricemia may be asymptomatic or symptomatic ◦ Risk of gout is only 0.6% in patients with serum urate concentrations < 7 mg/dL ◦ Risk rises to 30.5% in patients with serum urate concentrations > 10 mg/dL 3 Risk Factors Hyperuricemia → below factors can increase serum uric acid concentrations Age → much higher risk in elderly Obesity → 2x increased risk Diet → foods high in purines (alcohol, red meat, sugar, some types of seafood, yeast) Lifestyle → higher risk with sedentary lifestyle Gender → 2-3x more common in males 4  Etiology and Pathophysiology Production of uric acid is terminal step in degradation of purines → waste product Excess accumulation can be a result of overproduction or underexcretion of uric acid Examples of conditions associated with hyperuricemia: ◦ Diabetic ketoacidosis ◦ Lactic acidosis ◦ Heart failure ◦ Impaired kidney function ◦ Starvation ◦ Alcoholism ◦ Psoriasis ◦ Hypothyroidism ◦ Drugs: diuretics, ethanol, salicylates, cytotoxics, etc. ◦ Many others 5 Presentation – Acute Gout General: ◦ Acute, inflammatory, monoarthritis (single joint) ◦ First metatarsophalangeal joint is most commonly involved → podagra ◦ Any other lower extremity joint may be affected as well ◦ Rarely → wrist or finger Signs and symptoms ◦ Fever, intense pain, erythema, warmth, and swelling of involved joints Laboratory tests ◦ Elevated serum uric acid level and leukocytosis Other diagnostic tests ◦ Observation of MSU crystals in synovial fluid or tophus Patients may also present with nephrolithiasis (kidney stone) or gouty nephropathy 6 Diagnosis Definitive diagnosis ◦ Synovial fluid sample from joint to look for MSU crystals Clinical diagnosis: ◦ Monoarticular joint involvement of foot/ankle ◦ Previous similar episode ◦ Rapid onset of severe pain/swelling ◦ Erythema ◦ Male sex ◦ Hyperuricemia ◦ Presence of cardiovascular disease EULAR has published guidelines for gout diagnosis 7 Treatment 8 Goals of Treatment ◦ Terminate acute attack/relieve symptoms ◦ Prevent recurrent attacks of gouty arthritis ◦ Prevent complications associated with chronic MSU deposition into joints/tissues ◦ Minimize adverse effects of pharmacotherapy 9 General Approach to Treatment 1. Treatment of pain/inflammation 2. Use of ULT (urate-lowering therapy) to prevent recurrence 3. Use of anti-inflammatory prophylaxis to prevent acute gout attacks during initiation of ULT 10 Nonpharmacologic Treatment Non-pharmacologic aimed more at reducing risk of acute gout flare: ◦ Reduce dietary intake of purines ◦ Meats → especially red meats, organs (no liver, etc.), seafood ◦ Increase fluid intake ◦ Decrease salt and sugar consumption ◦ Restriction of alcohol intake ◦ Exercise and weight loss CAM: ◦ Consumption of cherry-containing products has been shown to have benefit in reducing risk of acute gout attack → limited data Adjuvant therapy for acute attack: ◦ Local ice application to affected joint ◦ Significantly greater pain reduction as compared to treatment without ice 11 12 Pharmacologic Therapy First-line therapies for acute gout flares: ◦ NSAIDs ◦ Corticosteroids ◦ Colchicine Each is used as monotherapy and is considered equally efficacious ◦ Treatment should begin as soon as possible after onset of flare ◦ Choice of therapy will depend on patient comorbidities If initial therapy is not adequate, may combine first-line therapy or use IL-1 inhibitor therapy (off-label use) 13 NSAIDs Little evidence to support one NSAID over another for the treatment of acute gout Three NSAIDs are FDA approved for treatment of gout: ◦ Indomethacin ◦ Naproxen ◦ Sulindac Other NSAIDs and COX2 inhibitors (celecoxib) are also effective Most important determinant of success is timing of initiation of therapy: ◦ The sooner the NSAID can be taken, the more likely it will be effective ◦ Patients may use the “pill in pocket” strategy → carry a dose of NSAID with them, so they have access if needed Resolution typically occurs within 5-8 days of initiating therapy 14 NSAIDs Adverse effects: ◦ GI → gastritis, bleeding, perforation ◦ Kidney → decreased GFR/acute kidney injury ◦ CV → sodium/fluid retention, elevated BP, potential risk for serious CV events ◦ CNS → dizziness, impaired cognitive function Caution use of NSAIDs in the following disease states: ◦ Peptic ulcer disease ◦ Heart failure ◦ Uncontrolled hypertension ◦ Impaired kidney function ◦ Coronary artery disease ◦ Currently receiving anticoagulants or antiplatelets 15 Corticosteroids May be given systemically or via intraarticular injection Systemic use is more convenient/accessible, however there is a risk of rebounding symptoms when stopping therapy abruptly ◦ More common after an extended dosing regimen Various dosing strategies: ◦ 0.5 mg/kg/day of prednisone or equivalent for 5-10 days, then stopping ◦ 0.5 mg/kg/day of prednisone or equivalent for 2-5 days, then taper dose down over 7-10 days ◦ Methylprednisolone dose pack → 6-day therapy, starting with 24 mg on day 1, then reducing by 4mg each day Short term adverse effects: ◦ Typically well-tolerated for the short duration of acute gout treatment ◦ Typically avoid in diabetes → increased blood sugar ◦ Caution in uncontrolled hypertension → fluid retention ◦ May cause difficulty sleeping 16 Colchicine Was used for many years to treat gout as an unapproved drug Colcrys® was FDA approved in 2009 → has since gone generic, but still is more costly than other options Should be started within the first 24 hours of acute attack ◦ Typically starts to resolve symptoms within hours of administration Dosing: 1.2 mg PO initially (2 tablets), followed by 0.6 mg PO 1 hour later ◦ Dose must be adjusted for patients on dialysis or on moderate/strong CYP3A4 inhibitors or PGP inhibitors ADEs: ◦ Primarily GI → nausea, vomiting, diarrhea ◦ Others → neutropenia, axonal neuromyopathy (higher risk in patients taking statins) 17 Prophylactic Therapy Urate Lowering Therapy (ULT) may be initiated for certain individuals to reduce the risk of future gout flares ACR guidelines recommend ULT therapy for the following: ◦ Frequent gout flares (2 or more per year) ◦ Presence of one or more tophi ◦ Radiologic evidence of damage attributable to gout Conditional ACR recommendations for initiating ULT (lower level of evidence) ◦ One or more gout flare, but less than 2 per year ◦ First gout flare with Stage 3 CKD or greater, serum uric acid > 9 mg/dL or urolithiasis 18 Prophylactic Therapy May be initiated safely during acute gout attack ◦ Evidence shows it does not prolong duration or worsen severity of attack compared to delayed initiation Goal: Reduce serum urate levels to < 6 mg/dL Must be long-term therapy → ACR guidelines recommend indefinite use of ULT when indicated Drugs: ◦ Xanthine oxidase inhibitors (preferred) ◦ Allopurinol 1st line ◦ Febuxostat 2nd line ◦ Uricosurics ◦ Probenecid ◦ Lesinurad ◦ Pegloticase 19 20 Xanthine Oxidase Inhibitors Impair conversion of hypoxanthine to xanthine and xanthine to uric acid Effective for both underexcreters and overproducers of uric acid Agents: ◦ Allopurinol (1st line) ◦ 100 mg PO daily as initial dose → titrate dose up until serum uric acid goal reached or max dose of 800mg/day reached ◦ Febuxostat (2nd line) ◦ 40 mg PO daily as initial dose → may titrate to maximum dose of 80 mg PO daily ADEs: ◦ Skin rash, leukopenia, GI upset, headache, urticaria, allopurinol hypersensitivity syndrome (very rare – but includes hepatitis, kidney failure, severe rash, and is fatal in 20-25% of patients) ◦ Febuxostat has been associated with an increase in all-cause mortality and CV mortality → boxed warning ◦ ACR guidelines recommend alternative agent in patients with history of CV disease or a new CVD-related event 21 Uricosurics Increase the renal clearance of uric acid → inhibit post-secretory renal proximal tubule reabsorption of uric acid ◦ May be added on to xanthine oxidase inhibitor therapy to meet serum uric acid goals ◦ Alternative agents for patients that are intolerant to xanthine oxidase inhibitors Agents: ◦ Probenecid ◦ 250 mg PO BID x 1-2 weeks, then 500 mg PO BID x 2 weeks, then titrate every 1-2 weeks until uric acid goal met or max dose of 2g reached ◦ Ineffective in patients with moderate-severe CKD (do not use if CrCl < 50 mL/min) ◦ Lesinurad ◦ Selective uric acid reabsorption inhibitor → inhibits urate transporter 1 in the proximal renal tubule ◦ Not currently available → manufacturer discontinued production in 2019 ADEs: ◦ Increased risk of nephrolithiasis (important to maintain adequate fluid intake while on these medications) ◦ GI irritation, rash Drug Interactions: ◦ Salicylates may decrease efficacy of uricosurics ◦ May decrease plasma concentrations of certain drugs → penicillins, cephalosporins, sulfonamides, indomethacin 22 Pegloticase (Krystexxa) Pegylated recombinant uricase → breaks down uric acid into allantoin ◦ Allantoin is water soluble and easily excreted Indicated for patients with chronic, severe gout and hyperuricemia (≥ 8 mg/dL) who fail or have a contraindication to conventional therapies ◦ Must have at least one of the following: ◦ Three or more gout flares in the last 18 months ◦ One or more tophi ◦ Joint damage due to gout 8mg IV infusion every 2 weeks → significantly higher cost than other therapies and inconvenient ◦ Minimum time for infusion is 120 minutes ◦ Must discontinue all other uric acid lowering therapies prior to starting this agent ◦ Premedicate patients with corticosteroids and antihistamines ◦ Due to potential for infusion-related reactions 23 Gout Prophylaxis During ULT Initiation All ULT agents may lead to an acute gout flare during initiation of therapy ◦ Due to remodeling of urate crystal deposits as a result of rapidly lowing urate concentrations ◦ May occur in up to 75% of patients starting ULT without prophylaxis ACR recommends prophylaxis of acute gout during the first 3-6 months of ULT initiation ◦ NSAIDs ◦ Colchicine ◦ Corticosteroids Lower doses than used for treatment of acute gout flare Longer duration of use (3-6 months) → more awareness of ADEs / preventative measures ◦ NSAIDs → use of PPI or H2RA to protect from GI problems ◦ Colchicine → monitor for GI ADEs ◦ Corticosteroids → higher risk of hyperglycemia, fluid retention, hypertension, osteoporosis, glaucoma, etc. 24 Summary Hyperuricemia is a condition of increased uric acid in the serum which may lead to acute arthritis, chronic gout, or kidney stones. Lifestyle modifications should be encouraged for all patients with hyperuricemia. Acute gouty arthritis responds well to NSAIDs, colchicine, and corticosteroids. Xanthine oxidase inhibitors are the treatment of choice for chronic hyperuricemia. 25