Gout & hyperuricemia

1. Gout & hyperuricemia

2. Definition • The term gout describes a disease spectrum including hyperuricemia, recurrent attacks of acute arthritis associated with monosodium urate crystals in leukocytes found in synovial fluid, deposits of monosodium urate crystals in tissues (tophi), interstitial renal disease, and uric acid nephrolithiasis. • A urate concentration greater than 7.0 mg/dL is abnormal and associated with an increased risk for gout.

3. Pathophysiology • In humans, uric acid is the end product of the degradation of purines. It serves no known physiologic purpose and is regarded as a waste product. The size of the urate pool is increased several fold in individuals with gout. • This excess accumulation may result from either overproduction or underexcretion. • Refer to patho course

4. Clinical presentation • Acute attacks of gouty arthritis are characterized by rapid onset of excruciating pain, swelling, and inflammation. The attack is typically monoarticular at first, most often affecting the first metatarsophalangeal joint (podagra), and then, in order of frequency, the insteps, ankles, heels, knees, wrists, fingers, and elbows. Attacks commonly begin at night, with the patient awakening from sleep with excruciating pain. The affected joints are erythematous, warm, & swollen. Fever and leukocytosis are common. Untreated attacks may last from 3 to 14 days before spontaneous recovery. • Although acute attacks of gouty arthritis may occur without apparent provocation, attacks may be precipitated by stress, trauma, alcohol ingestion, infection, surgery, rapid lowering of serum uric acid by ingestion of uric acid–lowering agents, and ingestion of certain drugs known to elevate serum uric acid concentrations.

5. Diagnosis • The definitive diagnosis is accomplished by aspiration of synovial fluid from the affected joint and identification of intracellular crystals of monosodium urate monohydrate in synovial fluid leukocytes.

6. Desired outcome • terminate the acute attack, • prevent recurrent attacks, • and prevent complications associated with chronic deposition of urate crystals in tissues.

7. Therapy Acute gout

8. Non-pharmacological treatment • Patients may be advised to reduce their intake of foods high in purines (e.g., organ meats), avoid alcohol, increase fluid intake, and lose weight if obese. • Joint rest for 1 to 2 days should be encouraged, and local application of ice may be beneficial.

9. NSAIDs • NSAIDs are the mainstay of therapy because of their excellent efficacy and minimal toxicity with short term use. • Therapy should be initiated with maximum recommended doses for gout at the onset of symptoms and continued for 24 hours after complete resolution of an acute attack, then tapered quickly over 2 to 3 days. Acute attacks generally resolve within 5 to 8 days after initiating therapy.

12. NSAIDs • Although the risk of GI complications is relatively small with short-term therapy, coadministration with a proton pump inhibitor should be considered in elderly patients and others at increased GI risk. NSAIDs should be used with caution in individuals with a history of peptic ulcer disease, heart failure, uncontrolled hypertension, renal insufficiency, coronary artery disease, or if they are receiving anticoagulants concurrently. • The efficacy and safety of cyclooxygenase-2 (COX-2) selective inhibitors (e.g., celecoxib) have not been fully assessed in gouty arthritis, but they are more costly than conventional NSAIDs and are unlikely to result in fewer GI complications because of the short duration of therapy.

13. Colchicine • is an antimitotic drug that is highly effective in relieving acute gout attacks but has a low benefit-toxicity ratio. The likelihood of success decreases substantially if treatment is delayed longer than 48 hours after symptom onset. • Oral colchicine causes dose-dependent GI adverse effects (N, V, and D) in 50% to 80% of patients before relief of the attack. • Non-GI adverse effects include neutropenia and axonal neuromyopathy, which may be worsened in patients taking other myopathic drugs (e.g., statins) or in those with renal insufficiency. Colchicine should not be used concurrently with macrolide antibiotics (especially clarithromycin) because reduced biliary excretion may lead to increased plasma colchicine levels and agranulocytosis. • Colchicine should be reserved for patients with insufficient relief, intolerance, or contraindications to NSAIDs. • The usual oral colchicine dose is 1 mg initially, followed by 0.5 mg every 1 hour until the joint symptoms subside, the patient develops abdominal discomfort or diarrhea, or a total dose of 8 mg has been given.

14. Colchicine • IV colchicine should be avoided because it is associated with serious AE • If considered necessary, the recommended initial IV dose is 2 mg (if renal function is normal) diluted in 10 to 20 mL of normal saline administered slowly over 10 to 20 minutes in a secure, free flowing IV line to avoid extravasation. This may be followed by two additional doses of 1 mg each at 6-hour intervals, with the total dose not exceeding 4 mg. After a full IV course, patients should not receive colchicine by any route for at least 7 days.

15. Corticosteroids • Corticosteroids may be used to treat acute attacks of gouty arthritis, but they are reserved primarily for patients with a contraindication or who are unresponsive to NSAID or colchicine therapy. Patients with multiple-joint involvement may also benefit. • The recommended dose is prednisone 30 to 60 mg (or an equivalent dose of another corticosteroid) orally once daily for 3 to 5 days. Because rebound attacks may occur upon steroid withdrawal, the dose should be gradually tapered in 5-mg increments over 10 to 14 days and discontinued.

16. Corticosteriod • A single intramuscular injection of a long-acting corticosteroid (e.g., methylprednisolone acetate) can be used as an alternative to the oral route if patients are unable to take oral therapy. If not contraindicated, low-dose colchicine can be used as adjunctive therapy to injectablecorticosteroids to prevent rebound flare-ups. • Intraarticular administration of triamcinolonehexacetonide 20 to 40 mg may be useful for acute gout limited to one or two joints. • Adrenocorticotropic hormone (ACTH) gel, 40 to 80 USP units, may be given intramuscularly every 6 to 8 hours for 2 to 3 days and then discontinued. Studies with ACTH are limited, and it should be reserved for patients with contraindications to first-line therapies (e.g., heart failure, chronic renal failure, history of GI bleeding).

17. Treatment Prophylactic therapy for intercritical gout

18. General approach • Prophylactic treatment can be withheld if the first episode of acute gouty arthritis was mild and responded promptly to treatment, the patient’s serum urate concentration was only minimally elevated, and the 24-hour urinary uric acid excretion was not excessive (less than 1,000 mg/24 hours on a regular diet). • If the patient had a severe attack of gouty arthritis, a complicated course of uric acid lithiasis, a substantially elevated serum uric acid (greater than 10 mg/dL), or a 24-hour urinary excretion of uric acid of more than 1,000 mg, then prophylactic treatment should be instituted immediately after resolution of the acute episode. • Prophylactic therapy is cost-effective for patients with frequent attacks of gouty arthritis (i.e., two or more attacks per year) even if the serum uric acid concentration is normal or only minimally elevated.

19. Cochicine • Colchicine given in low oral doses (0.5 to 0.6 mg twice daily) may be effective in preventing recurrent arthritis in patients with no evidence of visible tophi and a normal or slightly elevated serum urate concentration. • The oral dose should be reduced to no more than 0.6 mg daily or every other day in patients with renal or hepatic dysfunction. Treated patients who sense the onset of an acute attack should increase the dose to 1 mg every 2 hours; in most instances, the attack aborts after 1 or 2 mg. • Discontinuation of prophylaxis may be attempted if the serum urate concentration remains normal and the patient is symptom-free for 1 year.

20. Uric acid lowering therapy • Patients with a history of recurrent acute gouty arthritis and a significantly elevated serum uric acid concentration are probably best managed with uric acid–lowering therapy. • Colchicine, 0.5 mg twice daily, is sometimes given during the first 6 to 12 months of antihyperuricemic therapy to minimize the risk of acute attacks that may occur during initiation of uric acid–lowering therapy. • The therapeutic objective of antihyperuricemic therapy is to achieve and maintain a serum uric acid concentration less than 6 mg/dL, and preferably below 5 mg/dL.

21. Xanthineoxidase inhibitors • Allopurinol and its major metabolite, Because of the long half-life of its metabolite, allopurinol can be given once daily orally. It is typically initiated at a dose of 100 mg/day and increased by 100 mg/day at 1-week intervals to achieve a serum uric acid level of 6 mg/dL or less. Serum levels can be checked about 1 week after starting therapy or modifying the dose. Although typical doses are 100 to 300 mg daily, occasionally doses of 600 to 800 mg/day are necessary. The dose should be reduced in patients with renal insufficiency (200 mg/day for CLcr 60 mL/min or less, and 100 mg/day for CLcr 30 mL/mi or less). • Allopurinol is the antihyperuricemic drug of choice in patients with a history of urinary stones or impaired renal function, in patients who have lymphoproliferative or myeloproliferative disorders and need pretreatment with a xanthineoxidase inhibitor before initiation of cytotoxic therapy to protect against acute uric acid nephropathy, and in patients with gout who are overproducers of uric acid. • the major side effects of allopurinol are skin rash, urticaria, leukopenia, GI problems, headache, and increased frequency of acute gouty attacks with the initiation of therapy.

22. Uricoseuric drugs • Probenecid and sulfinpyrazone increase the renal clearance of uric acid by inhibiting the renal tubular reabsorption of uric acid. They should only beused in patients with documented underexcretion of uric acid. Therapy with uricosuric drugs should be started at a low dose to avoid marked uricosuria and possible stone formation. Maintenance of adequate urine flow and alkalinization of the urine with sodium bicarbonate or Shohl’s solution during the first several days of uricosuric therapy further diminish the possibility of uric acid stone formation. • Probenecid is given initially at a dose of 250 mg twice daily for 1 to 2 weeks, then 500 mg twice daily for 2 weeks. Thereafter, the daily dose is increased by 500-mg increments every 1 to 2 weeks until satisfactory control is achieved or a maximum dose of 2 g/day is reached. • The initial dose of sulfinpyrazone is 50 mg twice daily for 3 to 4 days, then 100 mg twice daily, increasing the daily dose by 100-mg increments each week up to 800 mg/day. • The major side effects associated with uricosuric therapy are GI irritation, rash and hypersensitivity, precipitation of acute gouty arthritis, and stone formation. These drugs are contraindicated in patients who are allergic to them and in patients with impaired renal function (CLcr <50 mL/min) or a history of renal calculi, and in patients who are overproducers of uric acid.

23. Evaluation of therapeutic outcome • A serum uric acid level . Repeat serum uric acid measurements are generally not necessary except during the titration phase of allopurinol to achieve a goal serum urate less than 6 mg/dL. • Patients with acute gout should be monitored for symptomatic relief of joint pain as well as potential adverse effects and drug interactions related to drug therapy. • Patients receiving hypouricemic medications should have baseline assessment of renal function, hepatic enzymes, complete blood count, and electrolytes. The tests should be rechecked every 6 to 12 months in patients receiving long-term prophylaxis. • Because of comorbidity with diabetes, dyslipidemia, hypertension, and stroke, the presence of increased serum uric acid levels or gout should prompt evaluation for cardiovascular disease and the need for appropriate risk reduction measures. Clinicians should also look for possible correctable causes of hyperuricemia (e.g., medications, obesity, and alcohol abuse).